Design, Synthesis, and in vitro and in vivo Evaluations of (Z)-3,4,5-Trimethoxystyrylbenzenesulfonamides/sulfonates as Highly Potent Tubulin Polymerization Inhibitors.

Newer therapeutics can be developed in drug discovery by adopting the strategy of scaffold hopping of the privileged scaffolds from known bioactive compounds. This strategy has been widely employed in drug-discovery processes. Structure-based docking studies illustrate the basic underlying concepts and reveal that interactions of the sulfonamide group and hydrophobic interactions are crucial. On the basis of this strategy, over 60 synthetic analogues were synthesized and evaluated for their cytotoxicity against the NCI panel of 60 human cancer cell lines; the majority of these compounds exhibited promising cytotoxicity with GI50 values ranging between 18 and 50 nm. Among these compounds, (Z)-N-[2,3-dimethoxy-5-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (7 a) and (Z)-N-[2-hydroxy-3-methoxy-6-(3,4,5-trimethoxystyryl)phenyl]-4-methoxybenzenesulfonamide (9 a) were found to be potent. Similar results were obtained against three human cancer cell lines with IC50 values ranging between 0.04 and 3.0 µm. Studies aimed at elucidating the mechanism of action of these new analogues revealed that they inhibited the in vitro polymerization of tubulin and disorganized the assembly of microtubules in HeLa and MCF-7cancer cells. Lead compounds 7 a and 9 a displayed notable in vivo antitumor activity in a HeLa tumor xenograft model. Our studies have resulted in the identification of a scaffold that can target tubulin polymerization, which should have significant potential toward the development of new antitumor drugs.

Synthesis and biological evaluation of cis-restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers.

A series of colchicine site binding tubulin inhibitors were synthesized by the modification of the combretastatin pharmacophore. The ring B was replaced by the pharmacologically relevant benzothiazole scaffolds, and the cis configuration of the olefinic bond was restricted by the incorporation of a triazole and tetrazole rings which is envisaged by the structural resemblance to a tubulin inhibitor like combretastatin (CA-4). 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 (9a and 9b) demonstrated an antiproliferative effect comparable to that of CA-4. 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. Western blot analysis revealed that these compounds accumulate more tubulin in the soluble fraction. The colchicine competitive binding assay and the molecular docking studies suggested that the binding of these mimics at the colchicine site of the tubulin is similar to that of CA-4. Moreover, the triggering of apoptotic cell death after mitotic arrest was investigated by studying their effect by Hoechst staining, Annexin-V-FITC assay, mitochondrial membrane potential, ROS generation and caspase-3 activation.

Embracing synthetic lethality of novel anticancer therapies.

INTRODUCTION: The significant challenge posed by cancer to human healthcare has led to the exploration of new approaches to combat it. Synthetic lethality (SL) is one such emerging area in the development of novel anticancer therapies. SL can be described as lethality (cell death) resulting from the combination of the two mutations, wherein the mutation in either of the two codependent genes in normal or cancer cells is viable. This concept is specifically being exploited in cancer research for selectively targeting specific tumor cells. AREAS COVERED: In this review, the authors summarize studies of SL-based novel anticancer therapies. The review highlights some of the selected advances in DNA damage response pathway-related SL pairs, particularly poly (ADP-ribose) polymerase (PARP) and SL pairs involved in mitochondrial death signaling pathways published in the last 3 years. EXPERT OPINION: Most of the currently used chemotherapeutic agents will destroy cells irrespective of whether they are cancer cells or fast growing normal cells; but SL is one of the approaches being developed with potential as a selective cancer therapy. PARP inhibitors, such as olaparib, are useful in BRCA mutated cancer cells and are also used in combination with other drug to enhance their efficacy. Research on PARP inhibitors is progressing at a good pace but there are still some significant challenges that must be addressed.

Synthesis of 2-anilinopyridine dimers as microtubule targeting and apoptosis inducing agents.

A series of 2-anilinopyridine dimers have been synthesized and evaluated for their anticancer potential. Most of the compounds have showed significant growth inhibition of the cell lines tested and compound 4d was most effective amongst the series displaying a GI50 of 0.99 µM specifically against the prostate cancer cell line (DU145). Studies to understand the mechanism of action of 4d indicates that it disrupts microtubule dynamics by inhibiting tubulin polymerization thereby arresting the cell cycle in G2/M phase. Competitive colchicine binding assay suggests that 4d binds into colchicine binding site of the tubulin. Further from some detailed biological studies like mitochondrial membrane potential, caspase-3 assay, DNA fragmentation analysis and Annexin V-FITC assay it is evident that 4d induces apoptosis.Molecular modeling studies provide an insight into the binding modes of 4d with colchicine binding site of tubulin and the data obtained correlates with the antiproliferative activity.

Design and synthesis of imidazo[2,1-b]thiazole-chalcone conjugates: microtubule-destabilizing agents.

A series of chalcone conjugates featuring the imidazo[2,1-b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF-7, A549, HeLa, DU-145 and HT-29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 µM. Among them, (E)-3-(6-(4-fluorophenyl)-2,3-bis(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)-1-(pyridin-2-yl)prop-2-en-1-one (11 x) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 µM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate (11 x) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell-cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase-3, DNA fragmentation analysis, and Annexin V-FITC assay. Moreover, molecular docking studies indicated that this conjugate (11 x) interacts and binds efficiently with the tubulin protein.

Synthesis and biological evaluation of 1,2,3-triazole linked aminocombretastatin conjugates as mitochondrial mediated apoptosis inducers.

A series of 1,2,3-triazole linked aminocombretastatin conjugates were synthesized and evaluated for cytotoxicity, inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant anticancer activity against some representative human cancer cell lines and two of the conjugates 6d and 7c displayed potent cytotoxicity with IC50 values of 53 nM and 44 nM against A549 human lung cancer respectively, and were comparable to combretastatin A-4 (CA-4). SAR studies revealed that 1-benzyl substituted triazole moiety with an amide linkage at 3-position of B-ring of the combretastatin subunit are more active compared to 2-position. G2/M cell cycle arrest was induced by these conjugates 6d and 7c and the tubulin polymerization assay (IC50 of 1.16 µM and 0.95 µM for 6d and 7c, respectively) as well as immunofluorescence analysis showed that these conjugates effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Colchicine competitive binding assay suggested that these conjugates bind at the colchicine binding site of tubulin as also observed from the docking studies. Further, mitochondrial membrane potential, ROS generation, caspase-3 activation assay, Hoechst staining and DNA fragmentation analysis revealed that these conjugates induce cell death by apoptosis.

Synthesis and anticancer activities of new Benzothiadiazinyl Hydrazinecarboxamides and Anilino[1,2,4]triazolo[1,5-b][1,2,4]thiadiazine 5,5-diones.

Two series of compounds (5-14 and 15-23) based on the scaffolds of 2-(1,1-dioxido-4-phenyl-4Hbenzo[e][1,2,4]thiadiazin-3-yl)-N-(4-methoxyphenyl)hydrazinecarboxamide (5) and 2-((4-methoxyphenyl)amino)-10-phenyl-10H-benzo[e][1,2,4]triazolo[1,5-b][1,2,4]thiadiazine 5,5-dioxide (15) respectively, were designed and synthesized. These compounds were tested for anticancer activity against various cancer cell lines including lung, ovary, prostate, breast and colon cancers. They exhibited moderate to good inhibitory activity against the above cell lines and compound 9 was found to be the most active one from these two series. Further studies showed that cancer cell growth inhibition by compounds 22 and 23 could be in part due to the inhibition of tubulin polymerization, with the IC50 values of 4.70 and 5.25 µM, respectively.

Synthesis, structure-activity relationship of novel substituted 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates as potential anti-mycobacterial and anticancer agents.

Series of 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives 7a-7zb, 8a-8d and 9a-9d were synthesized and screened for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H(37)Rv (MTB) and cytotoxicity against three human cancer cell lines including A549, SK-N-SH and HeLa. The results indicate that six compounds are more potent and 7za is most effective anti-mycobacterial derivative compared to the standard drugs Ethambutol and Ciprofloxacin. However, 12 compounds exhibited cytotoxicity against human neuroblastoma cell line; amongst them the compound 7v is most effective compared to the standard drug Doxorubicin. This is the first report assigning in vitro anti-mycobacterial, anticancer and structure-activity relationship for this new class of 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates.

Two new cytotoxic labdane diterpenes from the rhizomes of Hedychium coronarium.

The phytochemical investigation of the hexane extract of the Hedychium coronarium led to the isolation and identification of two new labdane diterpenes (1 and 2) along with 10 known metabolites (3-12). The structures of the new compounds were established on the basis of spectroscopic data analysis (1D and 2D NMR and MS). Cytotoxic activities of the isolates were studied against the A-549 (lung cancer), SK-N-SH (human neuroblastoma), MCF-7 (breast cancer) and HeLa (cervical cancer) cell lines.

Synthesis of 3,3-diindolyl oxyindoles efficiently catalysed by FeCl3 and their in vitro evaluation for anticancer activity.

A simple and highly efficient method has been developed for the synthesis of 3,3-diindolyl oxyindoles by the reaction of indoles with isatin or 5-fluoro isatin using a catalytic amount (5 mol%) of FeCl(3) at room temperature in a short reaction time in high yields. All these compounds were evaluated against a panel of five human cancer lines and most of them showed potent cytotoxicity. Compound 4b showed IC(50) of 4.7 and 5 microM against SK-N-SH and DU-145 cell lines, respectively, whereas 4c, 4d, 4f and 4k showed IC(50) of 2.2, 1.2, 3.6 and 3.6 microM, respectively, against DU-145 cell line. Interestingly, some of the compounds are selectively potent in prostate cancer (DU-145) with IC(50) values of 1.2-19.6 microM.

Total synthesis of (+/-)-elegansidiol, (+/-)-farnesiferol B, and (+/-)-farnesiferol D.

The racemic total synthesis of elegansidiol, farnesiferol B, and farnesiferol D has been obtained following a Diels-Alder approach. Gillman addition, cross metathesis reaction are the other key steps involved in the target synthesis.