Synthesis of DNA interactive C3-trans-cinnamide linked ß-carboline conjugates as potential cytotoxic and DNA topoisomerase I inhibitors.

A series of new C3-trans-cinnamide linked ß-carboline conjugates has been synthesized by coupling between various ß-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC50 values 13-45 nM. Moreover, the conjugates 8v and 8x were the most active against MCF-7 cells (14.05 nM and 13.84 nM respectively) and also even potent on other cell lines tested. Further, detailed investigations such as cell cycle analysis, apoptosis induction study, topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive topoisomerase I inhibitors.

Design and synthesis of 1,2,3-triazolo-phenanthrene hybrids as cytotoxic agents.

A series of new 1,2,3-triazolo-phenanthrene hybrids has been synthesized by employing Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. These compounds were evaluated for their in vitro cytotoxic potential against various human cancer cell lines viz. lung (A549), prostate (PC-3 and DU145), gastric (HGC-27), cervical (HeLa), triple negative breast (MDA-MB-231, MDA-MB-453) and breast (BT-549, 4T1) cells. Among the tested compounds, 7d displayed highest cytotoxicity against DU145 cells with IC50 value of 1.5±0.09µM. Further, the cell cycle analysis shown that it blocks G0/G1 phase of the cell cycle in a dose dependent manner. In order to determine the effect of compound on cell viability, phase contrast microscopy, AO/EB, DAPI, DCFDA and JC-1 staining studies were performed. These studies clearly indicated that the compound 7d inhibited the cell proliferation of DU145 cells. Relative viscosity measurements and molecular docking studies indicated that these compounds bind to DNA by intercalation.

Synthesis of different heterocycles-linked chalcone conjugates as cytotoxic agents and tubulin polymerization inhibitors.

A series of new heterocycles-linked chalcone conjugates has been designed and synthesized by varying different alkane spacers. These conjugates were tested for their in vitro cytotoxic potential against a panel of selected human cancer cell lines namely, lung (A549 and NCI-H460), prostate (DU-145 and PC-3), colon (HCT-15 and HCT-116), and brain (U-87 glioblastoma) by MTT assay. Notably, among all the tested compounds, 4a exhibited potent cytotoxicity on NCI-H460 (lung cancer) cells with IC50 of 1.48±0.19µM. The compound 4a showed significant inhibition of tubulin polymerization and disruption of the formation of microtubules (IC50 of 9.66±0.06µM). Moreover, phase contrast microscopy and DAPI staining studies indicated that compound 4a can induce apoptosis in NCI-H460 cells. Further, the flow-cytometry analysis revealed that compound 4a arrests NCI-H460 cells in the G2/M phase of the cell cycle. In addition, molecular docking studies of the most active compounds 4a and 4b into the colchicine site of the tubulin, revealed the possible mode of interaction by these new conjugates.

Design and synthesis of C3-tethered 1,2,3-triazolo-ß-carboline derivatives: Anticancer activity, DNA-binding ability, viscosity and molecular modeling studies.

A series of new DNA-interactive C3-tethered 1,2,3-triazolo-ß-carboline derivatives have been synthesized via 'click' reaction and evaluated for their in vitro cytotoxicity as well as DNA binding affinity. Interestingly, these hybrids have displayed potent in vitro cytotoxicity in comparison to Harmine against the HT-29 (colon cancer) and HGC-27 (gastric cancer) cell lines. The compounds 7f, 7k, 7n and 7s appear to be more effective against the HGC-27 cell line, among which compound 7f showed the highest cytotoxicity (5.44 ± 0.58, IC50 µM). The compounds 7e and 7f appear to be more active against the HT-29 cell line, among which compound 7f exhibited the highest cytotoxicity (3.67 ± 0.62, IC50 µM). To gain more insight into the DNA-binding ability, spectroscopic techniques such as UV-Visible, fluorescence and circular dichroism studies were performed. Viscosity measurements and molecular docking studies substantiate that these compounds indeed bind to DNA via the minor groove.

One-pot synthesis of podophyllotoxin-thiourea congeners by employing NH2SO3H/NaI: Anticancer activity, DNA topoisomerase-II inhibition, and apoptosis inducing agents.

A facile one-pot method for the synthesis of novel podophyllotoxin-thiourea congeners has been developed by using NH2SO3H/NaI system. Interestingly, 4ß-azido podophyllotoxin reduction with concomitant aryl isothiocyanates coupling under mild reaction conditions has been achieved. These compounds have been investigated for their in vitro cytotoxicity against A549, MDA MB-231, DU-145, LNCaP, and HGC-27 cancer cell lines. Some of the representative compounds have selectively exhibited cytotoxicity on DU-145 (human prostate cancer) cells and the most potent compound was 4a (IC50 of 0.50 ± 0.03 µM) with optimal safety therapeutic window (81.7 fold) on normal human prostate cell line (RWPE-1, IC50 of 40.85 ± 0.78). The flow-cytometric analysis of the compound 4a in prostate cancer cells indicated a strong G2/M-phase arrest and significant topoisomerase II inhibition activity. Furthermore, these compounds induce apoptosis as observed by Acridine Orange and Ethidium Bromide (AO/EB) staining and Annexin V binding assay. Molecular docking results of the title compounds with topoisomerase-IIα were presented as theoretical support for the experimental data.

Dithiocarbamate/piperazine bridged pyrrolobenzodiazepines as DNA-minor groove binders: synthesis, DNA-binding affinity and cytotoxic activity.

A new series of C8-linked dithiocarbamate/piperazine bridged pyrrolo[2,1-c][1,4]benzodiazepine conjugates (5a-c, 6a,b) have been synthesized and evaluated for their cytotoxic potential and DNA-binding ability. The representative conjugates 5a and 5b have been screened for their cytotoxicity against a panel of 60 human cancer cell lines. Compound 5a has shown promising cytotoxic activity on selected cancer cell lines that display melanoma, leukemia, CNS, ovarian, breast and renal cancer phenotypes. The consequence of further replacement of the 3-cyano-3,3-diphenylpropyl 1-piperazinecarbodithioate in 5b and 5c with 4-methylpiperazine-1-carbodithioate yielded new conjugates 6a and 6b respectively. In addition, the compounds 5c and 6a,b have been evaluated for their in vitro cytotoxicity on some of the selected human cancer cell lines and these conjugates have exhibited significant cytotoxic activity. Further, the DNA-binding ability of these new conjugates has been evaluated by using thermal denaturation (ΔTm) studies. The correlation between structure and DNA-binding ability has been investigated by molecular modeling studies which predicted that 6b exhibits superior DNA-binding ability and these are in agreement with the experimental DNA-binding studies.

DNA-binding affinity and anticancer activity of ß-carboline-chalcone conjugates as potential DNA intercalators: Molecular modelling and synthesis.

A new series of DNA-interactive ß-carboline-chalcone conjugates have been synthesized and evaluated for their in vitro cytotoxicity and DNA-binding affinity. It has been observed that most of these new hybrids have shown potent cytotoxic activities on A-549 (lung adenocarcinoma) cell lines with IC50 values lower than 10 µM. The hybrid 7b is more effective against some of the selected cancer cell lines with IC50 values less than 50 µM. In addition, compounds 7e, 7k, 7p-u has displayed significant elevation in ΔTm of DNA in comparison to Adriamycin, suggesting significant interaction and remarkable DNA stabilization. The DNA intercalation of these new hybrids has been investigated by fluorescence titration, DNA viscosity measurements, molecular docking as well as molecular dynamics and the results are in agreement with the thermal denaturation studies.

Design, synthesis and anticancer evaluation of tetrahydro-ß-carboline-hydantoin hybrids.

A series of new tetrahydro-ß-carboline-hydantoin hybrids have been designed and synthesized based on the structure of the known Eg5 inhibitor HR22C16. These compounds have been evaluated for their anticancer activity against lung (A549), cervical (ME180, HeLa), prostate (PC-3) and breast (MCF-7) cancer cell lines by MTT assay. These hybrids have displayed significant in vitro cytotoxicity in comparison to etoposide against PC-3, A549, and MCF-7 cell lines. The hybrids 3a, 3b, 3c, 3e, 3f, 3g, 4b, 4c, 4e and 4f appear to be more effective against the PC-3 cell line, among which compound 4b displayed the highest cytotoxicity (6.08 ± 0.2, IC50 µM). Based on these results, an attempt was made to rationalize their mechanism of action through cell cycle analysis studies. The flow-cytometric analysis of compound 4b in PC-3 cells indicated a G2/M cell cycle arrest. Molecular docking studies substantiate that these compounds indeed bind to the allosteric site of Eg5 formed from Glu116, Gly117, Glu118, Trp127, Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215 residues with the most potent compound 4b showing the most favorable interaction.

Asymmetric Michael addition of ketones to nitroolefins: pyrrolidinyl-oxazole-carboxamides as new efficient organocatalysts.

Chiral pyrrolidinyl-oxazole-carboxamides were synthesized and used as efficient new organocatalysts for the asymmetric Michael addition of ketones with nitroalkenes under solvent-free conditions. Gratifyingly, the corresponding Michael adducts were obtained in higher yields (up to 99%) and excellent stereoselectivities (up to >99/1 dr and 99% ee). Transition state models have been proposed to account for the high enantio- and diastereoselectivity of these Michael addition reactions and also the energetics have been investigated using density functional methods. These results support the preferential formation of syn-products by the approach of trans-ß-nitrostyrene through the re-face of anti-enamine.

Diverse Targeted Approaches to Battle Multidrug Resistance in Cancer.

The efficacy of successful cancer therapies is frequently hindered by the development of drug resistance in the tumor. The term 'drug resistance' is used to illustrate the decreased effectiveness of a drug in curing a disease or alleviating the symptoms of the patient. This phenomenon helps tumors to survive the damage caused by a specific drug or group of drugs. In this context, studying the mechanisms of drug resistance and applying this information to design customized treatment regimens can improve therapeutic efficacy as well as the curative outcome. Over the years, numerous Multidrug Resistance (MDR) mechanisms have been recognized and tremendous effort has been put into developing agents to address them. The integration of data emerging from the elucidation of molecular and biochemical pathways and specific tumor-associated factors has shown tremendous promise within the oncology community for improving patient outcomes. In this review, we provide an overview of the utility of these molecular and biochemical signaling processes as well as tumor-associated factors associated with MDR, for the rational selection of cancer treatment strategies.

Synthesis of podophyllotoxin linked ß-carboline congeners as potential anticancer agents and DNA topoisomerase II inhibitors.

A series of new podophyllotoxin linked ß-carboline congeners have been synthesized by coupling various substituted ß-carboline acids with 4ß-aminopodophyllotoxin. Evaluation of their anticancer activity against a panel of human cancer cell lines such as lung cancer (A549), prostate cancer (DU-145), MDA MB-231 (breast cancer), HT-29 (colon cancer) and HeLa (cervical cancer) suggested that 7i and 7j are the most cytotoxic compounds with IC50 values of 1.07 ±â€¯0.07 µM and 1.14 ±â€¯0.16 respectively against DU-145 cell line. Further, detailed biological studies such as cell cycle analysis, topoisomerase II inhibition, Comet assay, DNA binding studies and docking studies have revealed that these congeners are DNA interacting topoisomerase II inhibitors.

Targeting DNA Minor Groove by Hybrid Molecules as Anticancer Agents.

Agents which can recognize and bind specific sequences of DNA offer selective therapy through the modulation of specific transcription factors or genes. Recently, there has been renewed interest in the field of anticancer minor groove binders. This may be attributed to the fact that many compounds of this class have demonstrated significant antitumor activity against a wide variety of cancers in recent clinical trials. This review will discuss the recent efforts to overcome the drawbacks of existing minor groove binding anticancer agents through rational drug design based on scaffolds with known antitumor activity.

Synthesis of substituted phenanthrene-9-benzimidazole conjugates: Cytotoxicity evaluation and apoptosis inducing studies.

A series of new phenanthrene-9-benzimidazole conjugates has been synthesized by condensing phenanthrene aldehydes with various substituted o-phenylenediamines. The title compounds were evaluated for their in vitro cytotoxic potential against various human cancer cell lines like breast (BT-549), prostate (PC-3 and DU145), triple negative breast cancer (MDA-MB-453), and human colon cancer (HCT-116 and HCT-15) cells. Among the tested compounds, 10o displayed significant in vitro cytotoxic activity against PC-3 prostate cancer cells with an IC50 value of 6.32 ± 0.09 µM. Further, the cell cycle analysis indicated that it blocks G2/M phase of the cell cycle in a dose dependent manner. In order to determine the effect of the compound 10o on cell viability; phase contrast microscopy, AO/EB staining, DAPI staining, and DCFDA staining studies were performed. In these studies, apoptotic features were clearly observed indicating that the compound inhibited cell proliferation by apoptosis. JC-1 staining and annexin binding assays indicated the extent of apoptosis in PC-3 cells. Further, relative viscosity measurements and molecular docking studies indicated that these compounds bind to DNA by intercalation.

Synthesis of 2,3,6,7-tetramethoxyphenanthren-9-amine: An efficient precursor to access new 4-aza-2,3-dihydropyridophenanthrenes as apoptosis inducing agents.

A new route for the synthesis of novel 2,3,6,7-tetramethoxy phenanthrene amine precursor has been successfully accomplished. Subsequently, this amine precursor has been directly utilized for the synthesis of a new series of 4-aza-2,3-dihydropyridophenanthrene derivatives via a three component reaction with tetronic acid and substituted aldehydes. These compounds were evaluated for their cytotoxic potential against human lung (A549), prostate (PC-3 and DU145), breast (MDA-MB-231 and 4T1), gastric (HGC-27), colon (Caco-2) and cervical (HeLa) cancer cell lines. Compound 10l showed significant anticancer profile against DU145 cell line with an IC50 value of 2.6 ± 0.34 µM. Disruption of F-actin cytoskeleton structure and cell migration inhibition in DU145 cells clearly indicate that the tumor progression and metastasis are affected by this compound (10l). Cell cycle analysis revealed that it arrests the cells in G2/M phase. Acridine orange/ethidium bromide (AO/EB) staining, Hoechst staining and annexin-V binding assays showed that cell proliferation is inhibited through induction of apoptosis. Moreover, its treatment leads to collapse of the mitochondrial membrane potential (DΨm).