Rational design and synthesis of 2-anilinopyridinyl-benzothiazole Schiff bases as antimitotic agents.

Based on our previous results and literature precedence, a series of 2-anilinopyridinyl-benzothiazole Schiff bases were rationally designed by performing molecular modeling experiments on some selected molecules. The binding energies of the docked molecules were better than the E7010, and the Schiff base with trimethoxy group on benzothiazole moiety, 4y was the best. This was followed by the synthesis of a series of the designed molecules by a convenient synthetic route and evaluation of their anticancer potential. Most of the compounds have shown significant growth inhibition against the tested cell lines and the compound 4y exhibited good antiproliferative activity with a GI50 value of 3.8µM specifically against the cell line DU145. In agreement with the docking results, 4y exerted cytotoxicity by the disruption of the microtubule dynamics by inhibiting tubulin polymerization via effective binding into colchicine domain, comparable to E7010. Detailed binding modes of 4y with colchicine binding site of tubulin were studied by molecular docking. Furthermore, 4y induced apoptosis as evidenced by biological studies like mitochondrial membrane potential, caspase-3, and Annexin V-FITC assays.

Design and synthesis of cis-restricted benzimidazole and benzothiazole mimics of combretastatin A-4 as antimitotic agents with apoptosis inducing ability.

A series of colchicine site binding tubulin inhibitors were designed and synthesized by the modification of the combretastatin A-4 (CA4) pharmacophore. The ring B was replaced by the pharmacologically relevant benzimidazole or benzothiazole scaffolds, and the cis-configuration of the olefinic bond was restricted by the incorporation of a pyridine ring which is envisaged by the structural resemblance to a tubulin inhibitor like E7010. These compounds were evaluated for their antiproliferative activity on selected cancer cell lines and an insight in the structure activity relationship was developed. The most potent compounds (6c and 6l) demonstrated an antiproliferative effect comparable and superior to that of CA4 (GI50 up to 40nM). Mitotic cell cycle arrest in G2/M phase revealed the disruption of microtubule dynamics that was confirmed by tubulin polymerization assays and immunocytochemistry studies at the cellular level. The molecular docking studies suggested that the binding of these mimics at the colchicine site of the tubulin is similar to that of combretastatin A-4.

Synthesis of chalcone-amidobenzothiazole conjugates as antimitotic and apoptotic inducing agents.

A series of chalcone-amidobenzothiazole conjugates (9a-k and 10a,b) have been synthesized and evaluated for their anticancer activity. All these compounds exhibited potent activity and the IC(50) of two potential compounds (9a and 9f) against different cancer cell lines are in the range of 0.85-3.3 µM. Flow cytometric analysis revealed that these compounds induced cell cycle arrest at G2/M phase in A549 cell line leading to caspase-3 dependent apoptotic cell death. The tubulin polymerization assay (IC(50) of 9a is 3.5 µM and 9f is 5.2 µM) and immuofluorescence analysis showed that these compounds effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Further, Annexin staining also suggested that these compounds induced cell death by apoptosis. Moreover, docking experiments have shown that they interact and bind efficiently with tubulin protein. Overall, the current study demonstrates that the synthesis of chalcone-amidobenzothiazole conjugates as promising anticancer agents with potent G2/M arrest and apoptotic-inducing activities via targeting tubulin.

Synthesis of a new 4-aza-2,3-didehydropodophyllotoxin analogues as potent cytotoxic and antimitotic agents.

A series of novel conjugates of 4-aza-2,3-didehydropodophyllotoxins (11a-w) were synthesized by a straightforward one-step multicomponent synthesis that demonstrated cytotoxicity against five human cancer cell lines (breast, oral, colon, lung and ovarian). All the twenty three compounds (11a-w) have been examined for the inhibition of tubulin polymerization. Among these compounds, 11a, 11k and 11p exhibited inhibition of polymerization tubulin comparable to podophyllotoxin apart from disruption of microtubule organization within the cells. Flow cytometric analysis showed that these compounds (11a, 11k and 11p) arrested the cell cycle in the G2/M phase of cell cycle leading to caspase-3 dependent apoptotic cell death.

Rational Design and Synthesis of Naphthalene Diimide Linked Bis-Naphthalimides as DNA Interactive Agents.

A molecular modeling assisted rational design and synthesis of naphthalene diimide linked bis-naphthalimides as potential DNA interactive agents is described. Chemical templates incorporating naphthalene diimide as a linker in bis-naphthalimide motif were subjected to molecular docking analysis at specific intercalation and telomeric DNA G-quadruplex sites. Excellent results were obtained, which were better than the standards. A short and convenient synthetic route was employed to access these hybrids experimentally, followed by evaluation of their ability to cause thermal denaturation of DNA and cytotoxic properties along with ADME predictions. The obtained results provided useful insights and two potential molecules were identified for further development.

Synthesis and Biological Evaluation of 1,2,3-triazole tethered Pyrazoline and Chalcone Derivatives.

A series of pyrazoline derivatives and corresponding chalcone intermediates with substituents same as combretastatin-A4(CA-4) conjugated with triazole nucleus has been synthesized and evaluated for their anticancer potential. Sulphorhodamine B(SRB) assay indicated compound 12c to be the most active compound from the series with GI50 value of 6.7 µm against the human liver carcinoma cell line HepG2. Interestingly, the intermediate 11c exhibited more promising cytotoxicity demonstrating GI50 value of 1.3 µm against the prostate cancer cell line DU145. Compounds 11c and 12c caused accumulation of cells in G2/M phase and inhibited tubulin polymerization. Furthermore, these compounds reduce the mitochondrial membrane potential and activate caspases 3 and 9, thereby indicating their ability to trigger apoptosis.

p53-Mdm2 inhibitors: patent review (2009 - 2010).

INTRODUCTION: p53 plays a central role in protecting the integrity of the genome. Its activity is ubiquitously lost in cancers, either by inactivation of its protein (p53 pathway) or by mutation in the p53 gene, thereby indicating its importance in understanding cancer and as a therapeutic target. Activated p53 is known to induce cell cycle arrest thereby leading to apoptosis and has been the subject of intensive research in the area of medicinal chemistry. Efforts are in progress to synthesize a variety of scaffolds that could inhibit the p53-Mdm2 interaction by binding to Mdm2 in the region where p53 is likely to bind. These molecules have the potential to be developed as anticancer drug candidates and have been largely explored by both academia and industry. Interestingly, some of these molecules are in the early stage of clinical trials. AREAS COVERED: Areas covered in this review include patents relating to p53-Mdm2 inhibitors during the time period 2009 - 2010. The focus of the review was on small-molecule inhibitors. EXPERT OPINION: Inducing apoptosis in cancerous cells by the activation of p53 is an area that is being actively explored. There are strong indications that it could become a therapeutic method for the treatment of cancer. As a result, extensive research is being performed by both academia and industry. It is observed that small molecules that are present in early clinical trials are expected to be developed as potential drugs for cancer therapy.

Synthesis of terphenyl benzimidazoles as tubulin polymerization inhibitors.

A series of new terphenyl benzimidazoles (3a-z and 3aa-ad) were synthesized and evaluated for their anticancer activity. All the 30 compounds have shown moderate to good anticancer potency, however some of the compounds (3j, 3m-t and 3aa-ad) exhibited prominent anticancer potency with GI(50) values ranging from <0.1 to 9.72 µM. These compounds exhibit G2/M phase arrest and the analysis of tubulin by Western blot experiments in case of 3t and 3ad shows the disturbances that are caused in the ratio of soluble versus polymerized tubulin in cells. Compounds 3t and 3ad are the most promising candidates amongst the series and has the potential to be taken up for further detailed studies either alone or in combination with the existing therapies.

Synthesis and anticancer activity of 4ß-alkylamidochalcone and 4ß-cinnamido linked podophyllotoxins as apoptotic inducing agents.

A series of 4ß-alkylamidochalcone and 4ß-cinnamido linked podophyllotoxin congeners have been synthesized. All the twenty nine compounds were evaluated for anticancer activity against five human cancer cell lines (A-549, A375, MCF-7, HT-29 and ACHN). Some of the synthesized compounds showed good anticancer activity that is comparable to etoposide. The IC(50) of compounds 17a and 17f is 2.7 and 2.1 µM respectively against A-549 cancer cell line. Flow cytometric analysis showed that these two compounds arrested the cell cycle in the G2/M phase leading to caspase-3 dependent apoptotic cell death. Further, Hoechst 33258 staining and DNA fragmentation assay also suggested that 17a and 17f induced cell death by apoptosis.

Synthesis and antitumor evaluation of nitrovinyl biphenyls: anticancer agents based on allocolchicines.

A new class of nitrovinyl biphenyl compounds based on the structures of colchicines and allocolchicines were designed, synthesized, and shown to inhibit tubulin polymerization and cause mitotic arrest. A majority of these compounds were found to possess potent anticancer properties, with IC(50) values in the range of 0.05-7 µM, and are equally potent with colchicine in HeLa and MCF-7 cells. Compounds 14 e and 14 f inhibited tubulin assembly by more than 60 %, and flow cytometry studies indicated growth arrest of cells in the G(2)/M phase of the cell cycle in a concentration-dependent manner. Treatment of cells with 14 f resulted in upregulation of cyclin B1 and aurora kinase B mRNA levels, corresponding to growth arrest in the G(2)/M phase of the cell cycle as the mode of action.