Design, synthesis and in vitro cytotoxicity evaluation of indolo-pyrazoles grafted with thiazolidinone as tubulin polymerization inhibitors.

In the pursuit of potential and effective chemotherapeutic agents, a series of 2-((3-(indol-3-yl)-pyrazol-5-yl)imino)thiazolidin-4-ones was designed and synthesized, conjoining salient pharmacophoric properties for directing prominent cytotoxicity. The in vitro cytotoxicity evaluation revealed potent compounds with IC50 values <10 µM on tested human cancer cell lines. Compound 6c exhibited the highest cytotoxicity with an IC50 value of 3.46 µM against melanoma cancer cells (SK-MEL-28) and was highly cytospecific and selective towards cancer cells. The traditional apoptosis assays revealed morphological and nuclear alterations such as apoptotic body formation, condensed/horseshoe-shaped/fragmented/blebbing nuclei, and the generation of ROS. Flow cytometric analysis revealed effective early-stage apoptosis induction and cell-cycle arrest in the G2/M phase. In addition, the enzyme-based effect of 6c on tubulin showed the inhibition of tubulin polymerization (about 60% inhibition, IC50 was <1.73 µM). Moreover, molecular modeling studies affirmed the constant accommodation of compound 6c at the active pocket of tubulin, establishing many electrostatic and hydrophobic interactions with the active pocket's residues. The tubulin-6c complex was stable during the MD simulation for 50 ns with the recommended range of RMSD value (2-4 Å) for each pose.

Synthesis and cytotoxicity evaluation of DNA-interactive ß-carboline indolyl-3-glyoxamide derivatives: Topo-II inhibition and in silico modelling studies.

In a quest for effective cancer targeted drug therapy, a series of new ß-carboline tethered indole-3-glyoxylamide derivatives, conjoining salient pharmacophoric properties with prominent cytotoxicity, were synthesized. The in vitro cytotoxic ability of the compounds was established, and many of the compounds exhibited remarkable cytotoxicity (IC50 < 10 µM) on human cancer cell lines like HCT116, A549, SK-MEL-28, and MCF7. Precisely, compound 12x expressed the best cytotoxic potential against melanoma cancer cell line (SK-MEL-28) with an IC50 value of 4.37 µM. In addition, cytotoxicity evaluation against normal kidney cell line (NRK52E) entrenched the cytospecificity and selectivity index of 12x. The traditional apoptosis assays advised morphological and nuclear alterations such as apoptotic body formation, condensed/horseshoe-shaped/fragmented nuclei, and generation of ROS. The flow cytometric analysis revealed significant early and slight late-stage induction of apoptosis. The target-based physiochemical assays indicated the ability of compound 12x to bind with DNA and inhibition of Topoisomerase II. Moreover, molecular modeling studies affirm the excellent DNA intercalation potential and stabilized interactions of 12x with DNA base pairs. In silico prediction of physicochemical parameters revealed the promising drug-like properties of the synthesized derivatives.

Dithiocarbamation of spiro-aziridine oxindoles: a facile access to C3-functionalised 3-thiooxindoles as apoptosis inducing agents.

Herein, we report the first dithiocarbamation of spiro-aziridine oxindoles involving regiospecific ring-opening by using in situ generated nucleophilic dithiocarbamates as an instant source of sulfur. This approach afforded C3-functionalised-3-thiooxindoles in good to excellent yields with a wide substrate scope under catalyst-free and mild reaction conditions. These compounds were screened for their anticancer activity against a panel of human cancer cell lines, wherein compound 3u exhibited significant cytotoxic activity against human lung cancer cells with an IC50 value of 4.31 ± 1.88 µM. Phase contrast microscopy as well as different staining assays such as acridine orange/ethidium bromide (AO/EB), DAPI and DCFDA demonstrated the induction of apoptosis in A549 lung cancer cells after treatment with compound 3u. In addition, the clonogenic assay and migration assay demonstrated the ability of compound 3u to inhibit colony formation and cell migration, respectively, in A549 cells in a dose-dependent manner.

ß-Carboline tethered cinnamoyl 2-aminobenzamides as class I selective HDAC inhibitors: Design, synthesis, biological activities and modelling studies.

The effect of ß-carboline motif as cap for HDAC inhibitors containing cinnamic acid as linker and benzamides as zinc binding group was examined in this study. A series of ß-carboline-cinnamide conjugates have been synthesized and evaluated for their HDAC inhibitory activity and in vitro cytotoxicity against different human cancer cell lines. Almost all the compounds exhibited superior HDAC inhibitory activity than the standard drug Entinostat for in vitro enzymatic assay. Among the tested compounds, 7h displayed a noteworthy potency with an IC50 value of 0.70 ± 0.15 µM against HCT-15 cell line when compared to the standard drug Entinostat (IC50 of 3.87 ± 0.62 µM). The traditional apoptosis assays such as nuclear morphological alterations, AO/EB, DAPI, and Annexin-V/PI staining revealed the antiproliferative activity of 7h while depolarization of mitochondrial membrane potential by JC-1 was observed in dose-dependent manner. Cell cycle analysis also unveiled the typical accumulation of cells in G2M phase and sub-G1/S phase arrest. In addition, immunoblot analysis for compound 7h on HCT-15 indicated selective inhibition of the protein expression of class I HDAC 2 and 3 isoforms. Molecular docking analysis of compound 7h revealed that it can prominent binding with the active pocket of the HDAC 2. These finding suggest that the compound 7h can be a promising lead candidate for further investigation in the development of novel anti-cancer drug potentially inhibiting HDACs.

ß-Carboline-based molecular hybrids as anticancer agents: a brief sketch.

Cancer is a huge burden on the healthcare system and is foremost cause of mortality across the globe. Among various therapeutic strategies, chemotherapy plays an enormous role in overcoming the challenges of treating cancer, especially in late stage detection. However, limitations such as extreme side/adverse effects and drug resistance associated with available drugs have impelled the development of novel chemotherapeutic agents. In this regard, we have reviewed the development of ß-carboline-based chemotherapeutic agents reported in last five years. The review mainly emphasizes on the molecular hybrids of ß-carbolines with various pharmacophores, their synthetic strategies, and in vitro anticancer evaluation. In addition, the mechanisms of action, in silico studies, structural influence on the potency and selectivity among diverse cancer cell lines have been critically presented. The review updates readers on the diverse molecular hybrids prepared and the governing structural features of high potential molecules that can help in the future development of novel cytotoxic agents.

The microwave-assisted syntheses and applications of non-fused single-nitrogen-containing heterocycles.

Microwave technology has emerged as a great tool for the efficient synthesis of organic compounds and it provides opportunities for chemists to achieve chemical transformations that tend to be challenging using classical approaches. Additionally, N-heterocycles are well-known for their medicinal/biological significance, along with their applications as excellent building blocks in chemical synthesis. The dominance of N-heterocycles in drug molecules and other pharmacological agents makes them attractive scaffolds, which encourages chemists to develop a wide range of strategies towards the greener synthesis and functionalization of these heterocycles. In this regard, we have collated and discussed literature relating to the microwave-assisted synthesis and the modification of non-(benzo)fused single-nitrogen-containing N-heterocycles from the past decade. The role of the microwave technique and its benefits over the conventional approach have also been emphasized in terms of overall reaction efficiency, reaction time, yield, reduced side-product generation, neat and clean reactions, chemo-/regio-/enantio-selectivity, and the use of mild reagents/reaction conditions to achieve the objectives of green and sustainable chemistry.