الرئيسية / علماء مصر (الطيور المهاجرة) / Raed M.Maklad , Omar M. Aly ; El-Shimaa M. N. AbdelHafez ; Dalia A. Sayed. (AEA-Scholars)

Raed M.Maklad , Omar M. Aly ; El-Shimaa M. N. AbdelHafez ; Dalia A. Sayed. (AEA-Scholars)

Raed M.Maklad , Omar M. Aly ; El-Shimaa M. N. AbdelHafez ; Dalia A. Sayed. 

Association of Egyptian-American Scholars

Introduction:

Although most colchicine-building-site inhibitors reversibly bind to the tubulin, design and synthesis of irreversible inhibitors may lead to dramatic increase of anticancer activity. The technique involves covalent bon-formation with tubulin-receptor-pocket by alkylation of its nucleophilic aminoacid. moieties”e.g.terminal-NH2(Lysine)&SH-group(Cysteine)”using electrophilic ligands.Alkylatingys239caused cessation of tubullin- polymerization.

Scope:

-computer-aided screening of three series of potential antitubulin

agents(diacylhydrazines9a- c,bis-hydrazonoylchlorides10a-c and triazoles13a-b)via docking-study inside colchicine- binding-site of tubulin

-Synthesis of analogues with the best binding-interactions (schemes1&2)

maintaining essential-3,4,5-trimethoxyphenyl(ring A)with different

ringB-substitutions sometimes with alkylating linker (CI)C=NC(CI) as in bis-hydrazonoylchlorides10a-c

-Structure confirmation byIR, HNMR,DEPT-Q  C NMR.MS&elemental analysis.

-3D-structure-elucidation of some bis-hydrazonoylchlorides (stereochemistry of-C=N) using single-crystal X-ray-crystallallography.

-Screening of in-vitro anticancer &antitubulin activities of target compounds to prove their mechanism of action.

Conclusion:

– Diacylhydrazines 9a-c and triaryltriazoles13a-b are moderately cytotoxic against several cancer-cell lines.

– All tested bis-hydrazonoylchorides 10a, 10b1, 10b2 and 10c revealed potent antiproliferative activities against NCI-H522cell-line in the nano-molar-scale.

– The most potent derivative 10b2 has broken the record ofCA-4indicating the role of both3- OAc and OCH3substituents at ringB

– Tubulin inhibitory activity was proven as the mechanism-of-action of bis-hydrazonoylchlorides; irreversible inhibition is suggested(especially alkylation by C(CI)=N group,Scheme.3).

10c (having-3-OH,4-OMe-substitution)is still less-active than 10b2 indicating that 3- acetoxy group exerts good interaction with the receptor.

– Stereochemistry at-C=N-affects the appropriate orientation of

bis-hydrazonoylchlorides inside receptor which dramatically affects their anticancer activities,as shown by different cytotoxicities and tubulin-inhibitory-activities of both geometrical isomers10b1 and 10b2.

– Further investigation of bis-hydrazonoylchlorides is recommended for optimization of theirSAR-study and proving their tubulin-alkylation mechanism.

This article was published in 3alamaltanmya

sponsored by Future Builders International Academy

Led by Dr.Maha Fouad

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شاهد أيضاً

(Mohab S. El-Moiazen, Laila A. Mosaad (AEA-Scholars

Mohab S. El-Moiazen, Laila A. Mosaad Association of Egyptian-American Scholars Background: World Health Organization proved …

4٬201 تعليق

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