Metalloid and Metal-Based Drugs Presentation

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Metalloid and Metal-Based Drugs Hiroyuki Kobayashi Sep. 05. 2013Zakarian Group Meeting

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Id like to start my presentation.Todays topic is metalloid and metal-based drugs

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Metalloid-based drugsZakarian Group Meeting

#First session is metalloid based drugs2

Definition of metalloids

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Metalloids are the elements which possess the qualities of metals as well as non metals, hence they are also known as semimetals.

Metalloids in the periodic table are placed between the metals and the non metals and are located in a step-like structure.

Zakarian Group Meeting

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Here, Ill show you the definition of metalloids.Metalloids are the element which possess the qualities of metals as well as non metals, hence they are known as semimetals.Metalloids in the periodic table are placed between the metals and the non metals and are located in a step-like structure.

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Metalloids are usually characterized as metallic-looking brittle solids with intermediate to relatively good electrical conductivities, and each has the electronic band structure of a semimetal or semiconductor.

Properties of metalloids


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Chemically, they behave as non metals when they react with metals and behave as metals when they react with non metals.They are amphoteric oxides which means they can behave as basic oxides as well as acidic oxides.

Properties of metalloids


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Chemically, they behave as non metals when they react with metals and behave as metals when they react with non metals.They are amphoteric oxides which means they can behave as basic oxides as well as acidic oxides.

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Metalloids are too brittle to have any structural uses in their pure forms. Typical applications have instead encompassed their presence in, or specific uses as, glasses, fire retardants, alloying components, semiconductors, electronics, and optical storage media.

Uses of MetalloidsZakarian Group Meeting

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Metalloids are too brittle to have any structural uses in their pure forms.Typical application have instead encompassed their presence in, or specific uses as, glasses, fire retardants, alloying components, semiconductors, electronics and optical storage media.6

Metalloids are too brittle to have any structural uses in their pure forms. Typical applications have instead encompassed their presence in, or specific uses as, glasses, fire retardants, alloying components, semiconductors,electronics, and optical storage media.

They are also used in many biological processes.B, Si, As and Se are essential trace elements.All metalloid elements have toxic and medicinal propertiesto greateror lesser degrees.

Uses of MetalloidsZakarian Group Meeting

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They are also used in many biological processes.Boron, Silicon, Arsenic, Selenium are essential trace elements.All metalloid elements have toxic and medicinal properties to greater or lesser degrees.

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Application of metalloids in medicinal chemistryZakarian Group Meeting

#Next Ill show you the application of metalloids in medicinal chemistry.

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Arsenic compounds resemble in some respects those of phosphorus, which occupies the same group of theperiodic table.

Arsenic disruptsATPproduction through several mechanisms. By competing with phosphate, arsenate uncouplesoxidative phosphorylation.

The toxicity of arsenic toinsects,bacteriaandfungiled to its use as a wood preservative or as a feed additive. Arsenic was also used in various agricultural insecticides, termination and poisons.

Arsenic (As)Zakarian Group Meeting

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Arsenic Arsenic compounds resemble in some respects those of phosphorus which occupies the same group of the periodic table.Arsenic disrupts ATP production through several mechanisms.By competing with phosphate, arsenate uncouples oxidative phosphorylation.The toxicity of arsenic to insects, bacteria and fungi led to its use as a wood preservative or as a feed additive.Arsenic was also used in various agricultural insecticides, termination and poisons.Next Ill show you some examples.

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SalvarsanSalvarsan was the first chemotherapeutic compound that was introduced in 1910 as the effective treatment for syphilis. Salvarsan came with considerable risk of side effects, nevertheless demand for this compound remained very strong until 1943 when penicillin became available.

Angew. Chem. Int. Ed., 2005, 44, 941

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SalvarsanSalvarsan was the first chemotherapeutic compound that was introduced in 1910 as the effective treatment for syphilis.Salvarsan came with considerable risk of side effects, nevertheless demand for this compound remained very strong until 1943 when penicillin became available.In 1910, Paul Ehrlichdiscovered this compound, and until recently, it was believed that the structure featured an arsenic double bond.However, in 2005, an extensivemass spectral analysisshowed the actual structure is most likely to be a mixture of thecyclictrimerand pentamer.This monomer is generally assumed to be the active form, generated by in vivo oxidation of Salvarsan,

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RoxarsoneRoxarsone is widely used agriculturally as a chicken-feed additive to help prevent coccidiosis (a parasitic disease). About 1 million kgs of this compound were produced in 2006 in the US. In 2011, Pfizer voluntarily discontinued selling this product; the FDA's findings indicated elevated levels of arsenic in the livers of chickens consuming the arsonic acid.

Roxarsone can degrade in poultry litter leachates to produce more toxic inorganic forms of arsenic, such as arsenite and arsenate. Science of The Total Environment 2003, 302, 237

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RoxarsoneRoxarsone is widely used agriculturally as a chicken feed additive to help prevent coccidiosis (a parasitic disease).About 1 million Kgs of this compound were produced in 2006 in the US.In 2011, Pfizer voluntarily discontinued selling this products, FDAs findings indicated elevated levels of arsenic in the livers of chickens consuming the arsonic acid.Moreover, Roxarsone can photolitically degrade in the presence of nitrate to produce more toxic arsenite and arsenate.

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MelarsoprolMelarsoprol is now widely used in the treatment oflate-stage human African trypanosomiasis (sleeping sickness). Melarsoprol is extremely toxic to humans, causing life-threatening brain disease in about 510 percent of patients. The mechanism of action has never been entirely understood.

Sleeping sickness is aparasiticdiseasecaused byTrypanosoma brucei transmitted by thetsetse fly. About 48,000 people died of it in 2008. J. Infect. Dis., 2007, 195, 322

Trypanosoma

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MelarsoprolMelarsoprol is now widely used in the treatment of late-stage human African trypanosomiasis (sleeping sickness).Melarsoprol is extremely toxic to human, causing life-threatening brain disease in about 5-10 percent of patients.The mechanism of action has never been entirely understood.

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MelarsoprolMelarsoprol is now widely used in the treatment oflate-stage human African trypanosomiasis (sleeping sickness). Melarsoprol is extremely toxic to humans, causing life-threatening brain disease in about 510 percent of patients. The mechanism of action has never been entirely understood.

Sleeping sickness is aparasiticdiseasecaused byTrypanosoma brucei transmitted by thetsetse fly. About 48,000 people died of it in 2008. J. Infect. Dis., 2007, 195, 322

Sleeping sickness image

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Sleeping sickness is a parasitic disease caused by trypanosoma brucei transmitted by tsetse fly.About 48,000 people died of it in 2008.

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Boron atom has a vacant orbital which generates a new stable interaction between a boron atom and a donor molecule through a covalent bond.

In biology, borates have low toxicity in mammals (similar to table salt), but are more toxic toarthropodsand are used as insecticides.

Boric acidhas antiseptic, antifungal and antiviral properties and for this reasons is applied as a water clarifier in swimming pool water treatment and eye antiseptics.

Boron (B)Zakarian Group Meeting

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BoronBoron atom has a vacant orbital which generates a new stable interaction between a boron atom and a donor molecule through a covalent bond.In biology, borates have low toxicity in mammals (similar to table salt), but are more toxic to arthropods and are used as insecticides.Boric acid has antiseptic, antifungal and antiviral properties and for this reasons is applied as a water clarifier in swimming pool water treatment and eye antiseptics.

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Benzoxaboroles were developed by Anacor as oral treatment for human African trypanosomiasis (sleeping sickness). SCYX-7158 was shown to be safe and exhibited excellent in vivo PK and in vivo efficacy.Benzoxaboroles

Themechanismby whichSCYX-7158is trypanocidal is currently unknown. Other antifungal benzoxaboroles developed by Anacor inhibit Leucyl tRNA Synthetase by trapping tRNA on the fungal enzyme.

PLoS Neglected Tropical Disease 2011, 5, e1151

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BenzoxaborolesBenzoxaboroles were developed by Anacor as oral treatment for human African trypanosomiasis (sleeping sickness)SCYX-7158 was shown to be safe and exhibited excellent in vivo PK and in vivo efficacy.The mechanism by which SCYX-7158 is trypanocidal is currently unknown.Other antifungal benzoxaboroles developed by Anacor inhibit Leucyl tRNA synthetase by trapping tRNA on the fungal enzyme.

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Bortezomib (VELCADE )

Bortezomibis the first-in-classproteasome inhibitorfor the treatment of multiple myeloma (a plasma cell cancer) approved in the US in 2003. Multiple myeloma was an incurable malignancy that was diagnosed in about 15,000 people in the US each year.Bioorg. Med. Chem. Lett. 1998, 8, 333

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BortezomibBortezomib is the first in class proteasome inhibitor for the treatment of multiple myeloma (a plasma cell cancer) approved in the US in 2003.Multiple myeloma was an incurable malignancy that was diagnosed in about 15,000 people in the US each year.The earliest reported proteasome inhibitors included peptidyl aldehydes, which was expected to display poor metabolic stability and bioavailability.So a number of aldehyde replacements were examined in the attempt to overcome these shortcomings. The breakthrough came with synthesis of boronic acid which exhibits a 1000-fold enhancement in potency relative to the aldehyde.

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Bortezomib (VELCADE )

Bortezomibis the first-in-classproteasome inhibitorfor the treatment of multiple myeloma (a plasma cell cancer) approved in the US in 2003. Multiple myeloma was an incurable malignancy that was diagnosed in about 15,000 people in the US each year.Bioorg. Med. Chem. Lett. 1998, 8, 333

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The aldehyde compounds form hemi-acetal adducts with the active site threonine nucleophiles.The boronic acid compounds form stable tetrahedral intermediates with the threonine residue of proteasome.

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BNCT is a combination of treatment with boron and low energy neutrons. Radiotherapy using neutrons can get rid of glioblastoma cells. The boron molecules give off radiation within the brain tumor cells when the external neutron radiation hits them.Boron neutron capture therapy (BNCT)Radiat Res.2009, 172, 493

1. 10B compound which accumulates in the cancer cell is injected in a patient2. The neutron beam is irradiated to the lesion3. The cancer cells are selectively destroyed using a-particles which are generated by the 10B

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Boron neutrin capture therapy (BNCT)BNCT is a combination of treatment with boron and low energy neutrons.Radiotherapy using neutrons can get rid of glioblastoma cells. The boron molecules give off radiation within the brain tumor cells when the external neutron radiation hits them.Boron 10 compound such as p-Boronphenylalanine which accumulates in the cancer cells is injected in a patient.The neutron beam is irradiated to the lesionThe cancer cells are selectively destroyed using a-particles which are generated by the boron 10

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Silicon and carbon have similar properties because of their adjacent positions in group 14 of the periodic table.

There is no known intrinsic element-specific toxicity associated with organosilicon small molecules.

Silicones (silicon containing polymers) are used in the applications requiring high biocompatibility such as bandages, breast implants and contact lenses. Silicon (Si)Zakarian Group Meeting

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SiliconSilicon and carbon have similar properties because of their adjacent positions in groups 14 of the periodic table.There is no known intrinsic element-specific toxicity associated with organosilicon small molecules.Silicones (silicon containing polymers) are used in the applications requiring high biocompatibility such as bandages, breast implants and contact lenses.

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The medicinal applications of organosilicon molecule are particularly interesting because of differences in the chemical properties of organosilicon molecules compared to carbon-based functional groups.Chemical properties of siliconZakarian Group Meeting

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The medicinal applications of organosilicon molecule are particularly interesting because of differences in the chemical properties of organosilicon molecules compared to carbon-based functional groups. 20

The medicinal applications of organosilicon molecule are particularly interesting because of differences in the chemical properties of organosilicon molecules compared to carbon-based functional groups.Chemical properties of siliconZakarian Group MeetingChemical properties of organosilicon 1) The larger covalent radius of silicon contributes to about 20% longer bond lengths and different bond angles

2) The increased lipophilicity of organosilicon often enhances cell penetration and alters the potency and selectivity

3) The electropositive nature of silicon contributes to an electron deficient center in a molecule and reversed bond polarization

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Chemical properties of organosilicon are; The larger covalent radius of silicon contributes to about 20% longer bond lengths and different bond anglesThe increased lipophilocity of organosilicon often enhances cell penetration and alters the potency and selectivity.The electropositive nature of silicon contributes to an electron deficient center in a molecule and reversed bond polarization.

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Replacement of quaternary C with SiJ. Am. Chem. Soc., 2011, 133, 13844In the influenza A virus M2 proton channel inhibitor, hydrophobicity is known to play a critical role in improving the antiviral potency. The larger size and increased lipophilicity of silicon can provide a better hydrophobic contact between the inhibitor and the channel.

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Replacement of quaternary carbon with siliconIn the influenza A virus M2 proton channel inhibitor, hydrophobicity is known to play a critical role in improving the antiviral potency.The larger size and increased lipophilicity of silicon can provide a better hydrophobic contact between the inhibitor and the channel.

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Trialkylsilyl derivatives of drugsCamptothecin (CPT) is a natural quinoline alkaloid which inhibit DNA topoisomerase I for the treatment of solid tumors. CPT contains an a-hydroxyg-lactone, which reacts with H2O to form inactive ring-opened structure. The trialkylsilyl analogs have been designed to increase the stability of g-lactone.

Clin. Cancer. Res., 2005, 11, 3009

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Trialkylsilyl derivatives of drugsCamptothecin (CPT) is a natural quinoline alkaloid which inhibit DNA topoisomerase I for the treatment of solid tumors. Camptothecin contains an a-hydroxy-g-lactone, which reacts with H2O to form inactive ring-opened structure.The trialkylsilyl analogs have been designed to increase the stability of g-lactone.

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Trialkylsilyl derivatives of drugsCamptothecin (CPT) is a natural quinoline alkaloid which inhibit DNA topoisomerase I for the treatment of solid tumors. CPT contains an a-hydroxyg-lactone, which reacts with H2O to form inactive ring-opened structure. The trialkylsilyl analogs have been designed to increase the stability of g-lactone.

Clin. Cancer. Res., 2005, 11, 3009

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Trialkylsilyl derivatives have been shown to increase cell penetration, enhance blood stability and improve pharmacokinetics.Karenitecin which has the TBS moiety is currently undergoing phase III clinical trials in ovarian cancer patients.

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Silanol as an isostere of alcoholChem. Med. Chem., 2008, 3, 152A clinically useful antipsychotic drug, haloperidol is associated with a problematic metabolic pathway. The sila-analogs show a higher potency and selectivity than haloperidol and avoid the formation of a toxic metabolite.

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Silanol as an isostere of alcoholA clinically useful antipsychotic drug, haloperidol is associated with a problematic metabolic pathway.The sila-analogs show a higher potency and selectivity than haloperidol and avoid the formation of a toxic metabolile.The silahaloperidol shows a higher pootency at human dopamin D2 receptors and higher subtype selectivity at dopamin D1 and D2 than haloperidol.

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Silanol as an isostere of alcohol

A clinically useful antipsychotic drug, haloperidol is associated with a problematic metabolic pathway. The sila-analogs show a higher potency and selectivity than haloperidol and avoid the formation of a toxic metabolite.Metabolic pathwaysChem. Med. Chem., 2008, 3, 152

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Here, you can see the metabolic pathways.The metabolism of silahaloperidol has been studied and represents a particularly notable case where the incorporation of silicon significantly alters the metabolic fate compared to haloperidol.This haloperidol metabolite produces severe side effect, so controlling the metabolism can have significant advantages.Silaharoperidol avoids the common elimination pathway and undergoes oxidation at the carbon alpha to nitrogen to afford this, followed by ring-opening to eventually form non-toxic silanediol metabolite.

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Selenium belongs with oxygen and sulfur in thegroup of 16, so similarities in chemistry are to be expected.

The beneficial effects of selenium are strongly dependent on its concentration. Selenium salts are toxic in large amounts, but trace amounts are necessary for cellular function in many organisms, including all animals.

Selenium deficiency has been implicated in a number of serious or chronic diseases, such as cancer, diabetes, AIDS and tuberculosis. Selenium (Se) Zakarian Group Meeting

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SeleniumSelenium belongs with oxygen and sulfur in the group of 16, so similarities in chemistry are to be expected.The beneficial effects of selenium are strongly dependent on its concentration.Selenium salts are toxic in large amounts, but trace amounts are necessary for cellular function in many organisms, including all animals.Selenium deficiency has been implicated in a number of serious or chronic diseases, such as cancer, diabetes, AIDS and tuberculosis27

EbselenGen. Pharmac, 1995, 26, 1153Ebselen is a mimic of the antioxidant enzymes glutathione peroxidase (GPx), which is a potent scavenger of hydrogen peroxide as well as hydroperoxides. It is being investigated as a possible treatment for stroke, tinnitus and manic depression.

Glutathione peroxidase reduce freehydrogen peroxideto water. 2GSH + H2O2 GS-SG + H2O(GSH : glutathione)

GPx

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EbselenEbselen is a mimic of the antioxdant enzymes glutahione peroxidase (GPx), which is a potent scavenger of hydrogen peroxide as well as hydroperoxides.It is being investigated as a possible treatment for stroke, tinnitus and manic depression.

Glutathione peroxides reduce free hydrogen peroxide to water. And this ebselen can also reduce free hydrogen peroxide to water.

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AmselamineAmselamine, which is the seleno analog of amthamine, behave as a histamine H2-agonist with a higher potency than histamine and amthamine. Moreover amselamine exerts hardly any activity for histamine H1 and H3-receptors, which make it selective for the H2-receptor.

The selenazole ring of amselamine is somewhat more basic than the thiazole ring of amthamineBioorg. Med. Chem. Lett. 1994, 4, 1913

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AmselamineAmselamine, which is the seleno analog of the amthamine, behave as a histamine H2-agonist with higher potency than histamine and amthamine.Moreover amselamine exerts hardly any activity for histamine H1 and H3 receptors, which make it selective for the H2-receptor.

The pD2 value is derived from the 50% level of the maximum response of the histamine H2-agonistic dose response curve.Amselamine behaves as a full agonist with a pD2 value of 6.41 which makes it slightly more potent than histamine and amthamine.Although the mechanism of action has never been understood, they found the selenazole ring of amselamine is somewhat more basic than the thiazole ring of amthamine

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p-XSCMutation Research 2004, 551, 181p-XSC exerts chemopreventive activity for carcinogenesis in colon, lung, liver, intestine and oral tissues. It is has been hypothesized thatp-XSC is metabolized to the selenol, which inhibit tumor progression.

The selenol moiety has been hypothesized to be a critical selenium metabolite for anticancer activity in vivo

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P-XSC exerts chemopreventive activity for carciogenesis in colon, lung, liver, intestine and oral tissues.It is bas been hypothesized that p-XSC is metabolized to selenol, which inhibit tumor progression.

The selenol moiety has been hypothesized to be a critical selenium metabolite for anticancer activity in vivo. And it induces G1-cell cycle arrest and apoptosis via multiple signaling pathways, which may play a key role in methylselenol-induced inhibition of cancer cell proliferation and tumor cell invasion.

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Metal-based drugsZakarian Group Meeting

#Next, Id like to move on to metal-based drugs.31

Metals are essential for the biological processes of about 30-40% ofall known proteins including metalloenzymes which require metal cofactors.

Biological metalsZakarian Group Meeting

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Metals are essential for the biological processes of about 30-40% of all known proteins including metalloenzymes which require metal cofactors.

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The essential metals for humans are Na, K, Ca, Mg, Cu, V, Cr, Mn, Fe, Co, Ni, Zn, Mo and Cd. Low metal ion concentrations may be harmful for the body.


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Examples of specific types of metal deficiency include:

Fe Iron deficiency results in the loss of functional heme proteins, which are responsible for oxygen transport or utilization of oxygen. Zn Zinc deficiency due to diet can result in growth retardation.Cu Copper deficiency in infants results from infants with a poor diet and can cause heart disease.


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Examples of specific types of metal deficiency include:Fe Iron deficiency results in the loss of functional heme proteins, which are responsible for oxygen transport or utilization of oxygen. Zn Zinc deficiency due to diet can result in growth retardation.Cu Copper deficiency in infants results from infants with a poor diet and can cause heart disease.

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Metals have been used in treatments since ancient times. The Ebers Papyrus from 1500BC is the first written account of the use of metals for treatment and describes the use of Cu to reduce inflammation and the use of Fe to treat anemia.

Metal in medical treatmentZakarian Group Meeting

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Metals have been used in treatments since ancient times. The Ebers Papyrus from fifteen hundred BC is the first written account of the use of metals for treatment and describes the use of Cu to reduce inflammation and the use of Fe to treat anemia.

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Metals have been used in treatments since ancient times. The Ebers Papyrus from 1500BC is the first written account of the use of metals for treatment and describes the use of Cu to reduce inflammation and the use of Fe to treat anemia.

The application of metals to medicine is a rapidly developing field and novel therapeutic and diagnostic metal complexes are now having an impact on medical practice.

Metal in medical treatmentZakarian Group Meeting

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The application of metals to medicine is a rapidly developing field and novel therapeutic and diagnostic metal complexes are now having an impact on medical practice..

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Examples of metal-based drugsZakarian Group MeetingMetalProduct nameActive compoundMedical usage LiCamcolitLi2CO3manic depression MgMagnesiaMgOlaxative FeFenelminNa4Fe(II)(citrate)anemia CoCobaltamin SVitamin B12supplement ZnCalamineZnOskin ointment BaBaridolBaSO4X-ray contrast medium PtCisplatincis-[Pt(NH3)2Cl2]anticancer AuAuranofinAu(I)(PEt3)(acetylthioglucose)rheumatoidarthritis BiDe-NolK3[Bi(III)(citrate)2]antiulcer

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Examples of metal-based drugs is shown here.Ill show you some examples in detail in the next session.

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Application of metals in medicinal chemistryZakarian Group Meeting

#Next, Ill show you the application of metals in medicinal chemistry.

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Platinum-based antineoplasticdrugsarechemotherapy-agents to treatcancer.

They causecrosslinking of DNAas intrastrand crosslinks or DNA protein crosslinks.

The resultant crosslinking inhibitDNA repairand/orDNA synthesisin cancer cells.

The main dose-limiting side effects of cancer treatment with platinum compounds are nephrotoxicity and peripheralneurotoxicity.

Platinum (Pt)Zakarian Group Meeting

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PlatinumPlatinum-based antineoplasticdrugsarechemotherapy-agents to treatcancer. They causecrosslinking of DNAas intrastrand crosslinks or DNA protein crosslinks. The resultant crosslinking inhibitDNA repairand/orDNA synthesisin cancer cells.The main dose-limiting side effects of cancer treatment with platinum compounds are nephrotoxicity and peripheralneurotoxicity.

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Cisplatin is the first member of a class ofplatinum-containing anticancer drugs approved by FDA in 1978. It is used to treat various types of cancers, includingsarcomas, somecarcinomas,lymphomas, andgerm cell tumors. Cisplatin

Nature 1969, 222, 385

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CisplatinCisplatin is the first member of a class of platinum-containing anticancer drugs approved by FDA in 1978. It is used to treat various types of cancers, including sarcomas, some carcinomas, lymphomas and germ cell tumors.

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Cisplatin is the first member of a class ofplatinum-containing anticancer drug approved by FDA in 1978. It is used to treat various types of cancers, includingsarcomas, somecarcinomas,lymphomas, andgerm cell tumors. Cisplatin

Nature 1969, 222, 385

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Following administration, the chloride ligands are slowly displaced by water, in a process termed aquation. The aqua ligands are easily displaced, allowing the platinum atom to bind to bases. 41

Cisplatin is the first member of a class ofplatinum-containing anticancer drug approved by FDA in 1978. It is used to treat various types of cancers, includingsarcomas, somecarcinomas,lymphomas, andgerm cell tumors. Cisplatin

Cisplatin metabolites react with N(7) of guanine in DNA and form intrastrand crosslinks, which ultimately triggers apoptosis.Nature 1969, 222, 385

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These cisplatin metabolites react with N-7 position of guanine in DNA and form intrastrand crosslinks, which ultimately triggers apoptosis.

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Carboplatin and Oxaliplatin were subsequently introduced and have since gained popularity in clinical treatment due to its vastly reduced side-effects compared to cisplatin.Carboplatin and Oxaliplatin

Dalton Transactions 2010, 39, 8113

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Carboplatin and oxaliplatinCarboplatin and oxaliplatin were subsequently introduced and have since gained popularity in clinical treatment due to its vastly reduced side-effects compared to cisplatin.Cisplatin is the first generation of platinum drugs, which has strong side effects such as nephorotoxicity, nausea and vomiting.Carboplatin is the 2nd generation platinum drug approved in 1989, which has abidentatedicarboxylate ligand in the place of the twochlorideligands.Relative to cisplatin, nephrotoxic effects have been eliminated and nausea and vomiting are less severe.The third generation drug, oxaliplatin features thebidentateligand1,2-diaminocyclohexanein place of the twomonodentateamineligands.Oxaliplatin has the antitumjor activity against some cisplatin-resistant cancers.

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The first reports of gold drugs appeared in 1935, primarily to reduce inflammationand to slowdiseaseprogression in patients with rheumatoid arthritis.The mechanism by which these drugs affect arthritis is still unknown.

One noticeable side-effect of gold-based therapy is the coloring of the skin in shades of mauve to a purplish dark grey when exposed to sunlight.

The application of gold to medicine is called chrysotherapy.

Gold (Au)


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GoldThe first report of gold drugs appeared in 1935, primarily to reduce inflammation and to slow disease progression in patients with rheumatoid arthritis.The mechanism by which these drugs affect arthritis is still unknown.One noticeable side-effect of gold-based therapy is the coloring of the skin in shades of mauve to a purplish dark grey when exposed to sunlight.The application of gold to medicine is called chrysotherapy. 44

Auranofin is an oral drug approved for treatingrheumatoid arthritis in 1985. In 2012, Auranofin was identified as the protozoan agent of human amebiasis. It targets the thioredoxin reductase, preventing the reduction of thioredoxin to reactive oxygen-mediated killing. Auranofin (REDAURA )

Nature Medicine, 2012, 18, 956

Amebiasis is the fourth leading cause of death due to protozoan infections worldwide, resulting in 70,000 deaths annually. FDA has applied for approval to start clinical trials to treat amebiasis.Amebiasis

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AuranofinAuranofin is an oral drug approved for treating rheumatoid arthritis in 1985. In 2012 (last year), auranofin was identified as the protozoan agent of human amebiasis.It targets the thioredoxin reductase, preventing the reduction of thioredoxin to reactive oxygen mediated killing.

Amebiasis is the fourth leading cause of death due to protozoan infections worldwide, resulting in 70,000 deaths annually.FDA has applied for approval to start clinical trials to treat amebiasis.

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Bismuth is a highly acidic metal ion and may allow it to block Ca2+ channels and to disrupt the cell walls of bacteria.

These are also active against the bacterium Helicobacter pylori which is associated with the mucus layer of ulcers and cancers

Bismuth drugsare used to treat occasional upsetstomach,heartburn, andnausea. It is also used to treatdiarrhea.

Overexposure to bismuth can result in the formation of a black deposit on thegingiva, known as abismuth line.

Bismuth (Bi)


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BismuthBismuth is a highly acidic metal ion and may allow it to block Ca2+ channels and to disrupt the cell walls of bacteria.These are also active against the bacterium Helicobacter pylori which is associated with the mucus layer of ulcers and cancers. Bismuth drugsare used to treat occasional upsetstomach,heartburn, andnausea. It is also used to treatdiarrhea. Overexposure to bismuth can result in the formation of a black deposit on thegingiva, known as abismuth line.

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Bismuth subsalicylate is a drug used to treat temporary discomforts of the stomach and gastrointestinal tract. Commonly known aspink bismuth, it is the active ingredient in popular medications such asPepto-Bismol.

Salicylic acid produces its anti-inflammatory effects via suppressing the activity of cyclooxygenase(COX).BiClO remains in the stomach, and is in intimate contact with the mucus layer, where it stimulates mucus, bicarbonate and prostaglandin secretion. Bismuth subsalicylate

Antimicrobial Agents and Chemotherapy 1989, 33, 2075

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Bismuth subsalicylateBismuth subsalicylate is a drug to treat temporary discomforts of the stomach and gastrointestinal tract.Commonly known as pink bismuth, it is the active ingredient in popular medications such as Pepto-Bismol.In the gut, Bismuth subsalicylate is hydrolyzed into salicylic acid and bismuth oxycloride.Salicylic acid produces its anti-inflammatory effects via suppressing the activity of cyclooxygenase.Bismuth oxychloride remains in the stomach, and is in intimate contact with the mucus layer, where it stimulates mucus, bicarbonate and prostaglandin secretion. 47

InChina, mercury use was thought to prolong life, heal fractures, and maintain generally good health, although it is now known that exposure to mercury leads to serious adverse health effects.

Today, the use of mercury in medicine has greatly declined in all respects, especially in developed countries. Mercury compounds are found in some over-the-counter drugs, including topical antiseptics, stimulant laxatives,diaper-rashointment,eye drops, andnasal sprays.Mercury (Hg)Zakarian Group Meeting

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MercuryInChina, mercury use was thought to prolong life, heal fractures, and maintain generally good health, although it is now known that exposure to mercury leads to serious adverse health effects.Today, the use of mercury in medicine has greatly declined in all respects, especially in developed countries. Mercury compounds are found in some over-the-counter drugs, including topical antiseptics, stimulant laxatives,diaper-rashointment,eye drops, andnasal sprays.48

Merbromin is atopicalantisepticdrug discovered in 1918. This chemical soon became popular among parents and physicians for everyday antiseptic uses. It is readily available in most countries, but because of itsmercurycontent, it is no longer sold in the US, Germany and France.Merbromin

It is still an important antiseptic, particularly in developing nations, due to its unbelievably low cost.

Analytical and Bioanalytical Chemistry 2010, 397, 3525

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MerbrominMerbromin is a topical antiseptic drug discovered in 1918. This chemical soon became popular among parents and physicians for every day antiseptic uses.It is readily available in most countries, but because of its mercury content it is no longer sold in the US, Germany and France.Mercury moiety of merbromin is expected to react with thiol residues of enzyme to form a mercury sulfer bond to inhibit the enzyme activity.It is still an important antiseptic, particularly in developing nations due to its unbelievably low cost.

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As ruthenium is in the same group asiron, ruthenium complexes are able to take advantage of the bodys ability to efficiently transport and uptake of iron.

In recent years, ruthenium-based molecules have emerged aspromising antitumor and antimetastatic agents.

Ruthenium compounds are usually less toxic and no cross resistantthan platinum counterparts, therefore better tolerated in vivo.

In animal models, ruthenium compounds are effective in the treatmentof cancer types which cannot be treated by platinum compounds, most probably due to a different mode of action.Ruthenium (Ru)Zakarian Group Meeting

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Ruthenium As rethenium is the same group as iron, ruthenium complexes are able to take advantage of the bodys ability to effectively transport and uptake iron.In recent years, ruthenium-base molecules have emerged as promising antitumor and antimetastatic agents.Ruthenium compounds are usually less toxic and (no cross resistant) than platinum counterparts, therefore better tolerated in vivo.In animal models, ruthenium compounds are effective in the treatment of cancer types which cannot be treated by platinum compounds, most probably due to different modes of action.

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NAMI-A and KP1019 are two potential ruthenium drugs in phase II clinical trials. Despite their structural and chemical similarities, these two ruthenium complexes show distinct antitumor behaviors.NAMI-A and KP1019

NAMI-A induces cell arrest in the premitotic G (2)-M phase, strongly inhibits metastasis without effects on the primary tumor.

KP1019 induces apoptosis in colorectal tumor in which cisplatin is inactive, via intrinsic mitochondria apoptosis pathway.Cancer Chemother Pharmacol 2010, 66, 1

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NAMI-A and KP1019NAMI-A and KP1019 are two potential ruthenium drugs in phase II clinical trials.Despite their structural and chemical similarities, these two ruthenium complexes show distinct antitumor behaviors.

NAMI-A induces cells arrest in the premototic G2-M phase, strongly inhibits metastasis without effects on the primary tumor.KP1019 induces apoptosis in colorectal tumor in which cisplatin is inactive, via intrinsic mitochondria apoptosis pathway.

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Staurosporine is known as a nonspecific protein kinase inhibitor. By replacing the globular carbohydrate unit of staurosporine with Ru fragment, a series of selective inhibitors of GSK3 were discovered.Ru as Protein kinase inhibitorsJ. Am. Chem. Soc., 2004, 126, 13594

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Ruthenium as protein kinase inhibiorsStaurosporine is known as a nonspecific protein kinase inhibitor.By replacing the globular carbohydrate unit of staurosporine with ruthenium fragments, a series of selective inhibitor of GSK3 were discovered.The carbohydrate moiety forms hydrophobic contacts and hydrogen bond within the globular binding site.

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Staurosporine is known as a nonspecific protein kinase inhibitor. By replacing the globular carbohydrate unit of staurosporine with Ru fragment, a series of selective inhibitors of GSK3 were discovered.Ru as Protein kinase inhibitors

Ruthenium tends to form kinetically very inert coordinative bonds.The ruthenium complexes are stable under air and in waterJ. Am. Chem. Soc., 2004, 126, 13594

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This carbohydrate effect can be mimicked by an octahedral ruthenium complex. And this complex can be easily modified by changing ligands.The resulting ruthenium complex is more potent than staurosporine.Ruthenium tends to form kinetically very inert coordinative bonds.The rethenium complexes are stable under air and in water.

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Metalloid and metal based drugs are used as chemotherapeutic agents to combat Infectious diseases caused by pathogenic parasites, cancers, inflammation, mental disorders, infection etc.

It is clear that metalloid and metal based compounds offer new properties that cannot be found amongst purely organic agents.

The therapeutic application of metalloids and metals is still an unexplored area of research and continued work in this area is warranted.

SummaryZakarian Group Meeting

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This is the last slide.Metalloid and metal-based drugs are used as chemotherapeutic agents to combat infectious diseases caused by pathogenic parasites, cancers, inflammation, mental disorders, infection, etc. It is clear that metalloid and metal-based compounds offer new properties that cannot be found amongst purely organic agents. The therapeutic application of metalloids and metals is still an unexplored area of research and continued work in this area is warranted.

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Presentation Name | CONFIDENTIALZakarian Group Meeting

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AsAsAsAsHOH2NOHOHAsAsAsAsAsActiveformAssignedstructurebyEhrlichin1910RevisedstructuresbyNicholsonin2005(trimerandpentamermixture)HOOHOHNH2NH2H2NOHNH2OHNH2HOH2NOHHOH2NNH2SalvarsanoxidizedinvivoSalvarsanAsAsNH2OHHOH2NRoxarsoneAsOOHHOOHNO2AsOOHHOOHNO2NO2OHNO2+AsOHOHHONO2NO3hvNO3NO2hvAsOOOHOHphotolyticdegradationmechanismofroxarsoneinthepresenceofnitrate.RoxarsoneMelarsoprol(Injectiondrug)NNNH2NNH2HNSAsSOHMelarsoprol(Injectiondrug)NNNH2NNH2HNSAsSOH(PhaseI)SCYX-7158FCF3OHNOBOHNNNNNH2OOPOO-OtRNAOOOBH3ORtRNALeu-benzoxaboroleadductOBOHRNNONHOHNOHLeadcompoundKi=1600nMBortezomibKi=0.62nMNNONHOHNBOHOHNNONHOHNOHLeadcompoundKi=1600nMBortezomibKi=0.62nMNNONHOHNBOHOHOHNOHOOHNBOHOHO26SproteasomethreonineresiduehemiacetalformationcovalentbondformationHO26S26S26Sp-BoronphenylalanineNH2COOH10BOHHONH3+Cl-IC50=84.9MIC50=31.3MSpiraneamineSilaspiraneaminehydrophobicityactivitySiNH3+Cl-NNOOOOHCamptothecinlactoneform(active)carboxylateform(inactive)OH-H+NNOOOHOHOHNNOOOOHCamptothecinlactoneform(active)carboxylateform(inactive)OH-H+NNOOOHOHOHKarenitecin(PhaseIII)lipophilicitystabilityNNOOOOHSiMe2ButHaloperidolKi(hD2)=2.84nMhD2/hD1=37.6SilahaloperidolKi(hD2)=0.55nMhD2/hD1=294.5NHOOFClselectivityactivitySiNHOOFClNOFClSiNOHHOClFaneurotoxinpyridinium(sourceofparkinsonism)NOFClSiNOFClHOOHEbselen(PhaseIII)SeNOSeNOSeNOSeNOOHOSGH2O2H2OGSHGSHGS-SGEbselenNNHNH2NSNH2NH2HistamineAmthamineAmselaminepD2=6.14pD2=6.21pD2=6.41ThepD2valuesarederivedfromthe50%levelofthemaximumresponseofthehistamineH2-agoniticdoseresponsecurve.NSeNH2NH2p-XSC1,4-phenylenebis(methylene)selenocyanateSeCNNCSep-XSCSeCNNCSeSeSGGSSeSeHHSe2HCNGSSG2GSHselenolderivativeglutathioneconjugateG1cellcyclearrestCaspase-mediatedapoptosisInhibitionoftumorcellinvasionCisplatinPtH3NClH3NClPtH3NOH+H3NClcytoplasmPtH3NOH+H3NOH+HNNOH2NNRNNHNONH2NRNPtH3NNH3PtGNH3NH3GDNAGuaninePtH3NClH3NClCisplatin1stgeneration)1978PtH3NOH3NOOOCarboplatin(2ndganeration)1989Oxaliplatin(3rdgeneration)1996PtH2NONH2OOOTreatingvarioustypesofcancersSideEffect:Nephrotoxicity,nauseaandvomitingRelativetocisplatin,nephrotoxiceffectshavebeeneliminatedNauseaandvomitingarelesssevereActiveagainstsomecisplatin-resistantcancersAuranofinOOOOSOOOOOAuPBismuthsubsalicylateOOOBiOHOOOBiOHOOHOHBiClO+HClinthegutsalicylicacidMerbrominOCOOHOBrBrHOHgHOOCOOHOBrBrHOHgHOSHpH6.6OCOOHOBrBrHOHgSMerbrominisexpectedtoreactwiththiolresiduesofenzymetoformamercurysulfurbondtoinhibittheenzymeactivity.NAMI-AKP1019RuNSNOClClClClRuNNNClClClClNHNNNOONHMeMeOStaurosporineRucomplexGSK3IC50=50nMGSK3IC50=3nMHNNONRuCOOHNNNOOHNOshapemimicModificationiseasy(bychangingligands)HNNONRuCBADglobularunit

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Metalloid and Metal-Based Drugs Presentation