4ß-[4'-(1-(Aryl)ureido)benzamide]podophyllotoxins as DNA topoisomerase I and IIα inhibitors and apoptosis inducing agents.

A series of 4ß-[4'-(1-(aryl)ureido)benzamide]podophyllotoxin congeners (11a-l) were synthesized and evaluated for their cytotoxic activity against six human cancer cell lines. Some of the compounds like 11a, 11h, 11k and 11l showed significant anti-proliferative activity in Colo-205 cells and were superior to etoposide. The flow-cytometric analysis studies indicated that these compounds show strong G1 cell cycle arrest, as well exhibited improved inhibitory activities on DNA topoisomerase I and IIα enzymes. These compounds induce apoptosis by up regulating caspase-3 protein as observed by ELISA and Western blotting analysis. In addition, a brief structure-activity relationship studies within the series along with docking results of representative compounds 11a, 11h, 11k, 11l were presented.

Synthesis and biological evaluation of combretastatin-amidobenzothiazole conjugates as potential anticancer agents.

A series of combretastatin-amidobenzothiazole conjugates have been synthesized and evaluated for their anticancer activity. All these compounds exhibited significant anticancer activity and the most potent compound (11a) showed GI(50) values ranging 0.019-11 µM. Biological studies such as cell cycle distribution, effect on tubulin polymerization and effect on ERK signalling pathway have been examined in MCF-7 cell line. FACS analysis revealed that these compounds induced cell cycle arrest at G2/M phase. Compound 11a showed significant effect on tubulin polymerization and affected the ERK signalling pathway that result in the decreased levels of ERK1/2, p-ERK and c-Jun proteins. Docking experiments have shown that the active molecules interact and bind well in the ATP binding pocket of ERK protein.

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 and biological evaluation of 4ß-sulphonamido and 4ß-[(4'-sulphonamido)benzamide]podophyllotoxins as DNA topoisomerase-IIα and apoptosis inducing agents.

A series of new 4ß-sulphonamido and 4ß-[(4'-sulphonamido)benzamide] conjugates of podophyllotoxin (11a-j and 15a-g) were synthesized and evaluated for anticancer activity against six human cancer cell lines and found to be more potent than etoposide. Some of the compounds 11b, 11d and 11e that showed significant antiproliferative activity in Colo-205 cells, were superior to etoposide. The flow cytometric analysis indicates that these compounds (11b, 11d and 11e) showed G2/M cell cycle arrest and among them 11e is the most effective. It is observed that this compound (11e) caused both single-strand DNA breaks as observed by comet assay as well as double-strand DNA breaks as indicated by γ-H2AX. Further 11e showed inhibition of topo-IIα as observed from Western blot analysis and related studies. Compounds caused activation of ATM as well as Chk1 protein indicating that the compound caused effective DNA damage. Moreover activation of caspase-3, p21, p16, NF-kB and down regulation of Bcl-2 protein suggests that this compound (11e) has apoptotic cell death inducing ability, apart from acting as a topo-IIα inhibitor.

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 biological evaluation of 4ß-acrylamidopodophyllotoxin congeners as DNA damaging agents.

A series of new 4ß-acrylamidopodophyllotoxin derivatives (13a-o) were synthesized by coupling of substituted acrylic acids (10a-l and 11m-o) to the 4ß-aminopodophyllotoxin. The synthesized derivatives 13a-o were evaluated for their cytotoxicity against five human cancer cell lines (breast, oral, colon, lung and ovarian). These podophyllotoxin conjugates have shown promising activity with GI50 values ranging from <0.1 to 0.29 µM. Some of the compounds 13j, 13k and 13l that showed significant antiproliferative activity were also evaluated for related cytotoxic effects in MCF-7 cells, and compared to etoposide. These compounds (13j, 13k and 13l) showed G2/M cell cycle arrest and the apoptotic event was found to be due to both the single-strand DNA breaks as observed by comet assay as well as double-strand breaks as observed by the large accumulation of gamma H2AX foci.

Synthesis of 4ß-carbamoyl epipodophyllotoxins as potential antitumour agents.

A series of new 4ß-carbamoyl epipodophyllotoxin analogues have been synthesized and evaluated for their anticancer activity against eleven cancer cell lines including Zr-75-1, MCF7, KB, Gurav, DWD, Colo 205, A-549, Hop62, PC3, SiHa and A-2780. Most of the compounds exhibited better growth-inhibition activities against tested cell lines than that of etoposide. Further, compounds 6g and 6i are also evaluated for their DNA topoisomerase-II (topo-II) inhibition activity and they exhibited significant inhibition of topo-II catalytic activity comparable to etoposide.

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.

An efficient one-pot synthesis of benzothiazolo-4ß-anilino-podophyllotoxin congeners: DNA topoisomerase-II inhibition and anticancer activity.

An efficient one-pot iodination methodology for the synthesis of benzothiazolo-4ß-anilino-podophyllotoxin (5a-h) and benzothiazolo-4ß-anilino-4-O-demethylepipodophyllotoxin (6a-h) congeners has been successfully developed by using zirconium tetrachloride/sodium iodide. Interestingly, this protocol demonstrates enhancement of stereoselectivity apart from the improvement in the yields in comparison to previous methods reported for such related podophyllotoxin derivatives. These compounds have been designed and synthesized using association strategy by coupling of 4ß-podophyllotoxin and 4ß-demethylepipodophyllotoxin with a variety of substituted aminoaryl benzothiazoles. Some of the representative compounds have been evaluated for their cytotoxicity against selected human cancer cell lines and DNA topoisomerase-II inhibition activity.

Synthesis of 4ß-N-polyaromatic substituted podophyllotoxins: DNA topoisomerase inhibition, anticancer and apoptosis-inducing activities.

A new class of 4ß-N-polyaromatic substituted podophyllotoxin congeners have been synthesized and evaluated for their DNA topoisomerase-II (topo-II) inhibition as well as anticancer potential in some human cancer cell lines. The ease of synthesis and interesting biological activities make the present series of polyaromatic-podophyllotoxin congeners as a promising new structure for the development of new anticancer agents based on podophyllotoxin scaffold.