Fiorillo Saycs 2015

Novel 13-(di)arylalkyl berberines with

antiproliferative activityGaetano Fiorillo, Franco Buzzetti,

Paolo Lombardi, Tanjia Monir Syeda

via G. Di Vittorio 70, 20026 Novate Milanese, Milano, Italy

Email: staff@naxospharma.eu

Rimini 27-29 October 2015

BerberineBackground History

Bitter-tasting isoquinoline quaternary alkaloid extracted

from plants of the genus Berberis, Coptis and others.

In use in the Ayurvedic and Chinese medicines since hundreds of years.

It shows diverse pharmacological activities:

Anti-microbial/parasitic,

Anti-diarrheal, anti-inflammatory,

Anti-arryhthmic,

Cholesterol-lowering

Anticancer

The precise molecular basis of its many biological

activities are still debated

Modulation of protein expression by interaction with

nucleic acids is postulated

The interactions between berberine and nucleic acids,

reported since 1962, could lead to its anticancer effect

Mazzini, S. et al, Bioorg Med Chem,

2003, 505–514

(NMR Studies)

Ferraroni, M. et al, Chem. Commun.

2011, 4917-4919

(RX studies)

intercalation

minor groove binding

BerberineDNA Interaction

Berberine represents an interesting and

attractive natural lead compound

Chemical modifications might select more

specific medical indications resulting in

derivatives with better (or different)

biological effects compared to the parent

berberine

Performing rational chemical modifications of

berberine structure led to a new class of

derivatives with antitumour properties

Chemical

Programme

Berberin

e

BerberineAnticancer Properties

Since aromatic interactions are ubiquitous in nature, and their geometry is relevant for the molecular recognition in biological system, that could result in better (or different)

biological effects with respect to the parent Berberine

Chemical

Programme

from very low to low yields - better with activated halides or iodides - berberine back from loss of acetone major by-product

Alkylation of enamine (7,8-dihydroberberine)

Berberine derivativesSynthetic Methods

from low to moderate yields -berberine and tetrahydroberberinefrom disproportionation of enamineas major by-products

generally from good to very good yields

Uncommon aldehyde-enamine condensation1,2

2 Iwasa, K, et al., Planta Medica, 1997, 196 1 Cook, AG, Enamines Synthesis, Structure and reaction, 1988, pag 200-201

Berberine derivativesSynthetic Methods

1) Commercially available aldehydes

2) Commercially available alcohol followed by oxidation

(PCC or TEMPO)

3) Homologation starting from aldehydes 1) & 2)

Of course, most of starting materials, reagents, solvents,

and disposables are from

Berberine DerivativesAldehyde Intermediates

Another route was used

Berberine DerivativesAldehyde Intermediates

Berberine

DerivativesBinding to DNA

1.770.35

2.11

11.01

7.6 7.586.8

0

2

4

6

8

10

12

Kix

10

-5(M

-1)

Binding costants of NAXs 1

1.770.48 0.51

7.07

10.048.90

7.48

0

2

4

6

8

10

12

Kix

10

-5(M

-1)

Binding costants of NAXs2

1D. Bhowmik, M. Hossain, F. Buzzetti, R. D’Auria, P. Lombardi, G.S.Kumar, J. Phys. Chem. B, 2012, 116, 2314−24.2D. Bhowmik, F. Buzzetti, G. Fiorillo, F. Orzi, T. Syeda Monir, P. Lombardi, G.S. Kumar, Med. Chem. Comm., 2014, 5, 226-31.

n = 3

n = 4

Berberine

DerivativesBinding to DNA

0

2

4

6

8

10

12

Ki x

10

-5 (

M-1

)

Pyridylalkyl derivatives

S. Chatterjee, S. Mallick, F. Buzzetti, G. Fiorillo, T. M. Syeda, Paolo Lombardi, K. Das Saha, G. S. Kumar, RCS Adv., 2015, 5, 90632

n = 5

Berberine DerivativesAntiproliferative effects

STO, MESOII = peritoneal mesothelima cell linesMSTO = pleural mesothelioma cell line

0123456789

IC50 [m

M]

Mesothelioma cell lines

STO

MESOII

MSTO

0

1

2

3

4

5

6

7

8

9

IC5

0 [m

M]

Mesothelioma cell lines

STO

MESOII

MSTO

Berberine DerivativesAntiproliferative effects

Human breast adenocarcinomacell line

Human liver hepatocellularcarcinoma cell line

S. Chatterjee, S. Mallick, F. Buzzetti, G. Fiorillo, T. M. Syeda, Paolo Lombardi, K. Das Saha, G. S. Kumar, RCS Adv., 2015, 5, 90632

In the Chinese traditionalmedicine, Berberine has been used for the treatment of hepatocellular carcinoma;

Berberine derivatives have an in vitro better effect.

Conclusions

The promising data obtained on relevant cancer cell lines, shown here andin other scientific reports, support an active role of BBR in inhibiting cancer cell

proliferation.

To improve this relevant property, many derivatives (essentially with (hetero)aromatic groups in the position 13 of the alkaloid skeleton) have been designed and synthesized.

In general, derivatives proved to be more efficient than the lead compound, thus opening new perspectives for drug discovery

Work performed so far has led to the identification of some candidate compounds with a profile that would justify the progression to late preclinicaldevelopment studies.

Aknowledgements: Financial supports were provided by Ministero dello Sviluppo Economico (Grant. 01709 ) under the 6th call of the EuroTransBio initiative, transnational project BERTA (BERberine as antiTumour Agents)