N. Maruthi Kumar

Synthesis and biological evaluation of indolyl chalcones as antitumor agents

A series of indolyl chalcones were synthesized and evaluated in vitro for their anticancer activity against three human cancer cell lines. Compounds 3b-d, 3h, 3j, 3l, 3m, 4g, and 4j showed significant cytotoxicity, particularly, indolyl chalcones 3l and 3m were identified as the most potent and selective anticancer agents with IC(50) values 0.03 and 0.09 microM, against PaCa-2 cell line, respectively.

Novel bis(indolyl)hydrazide–hydrazones as potent cytotoxic agents

A series of bis(indolyl) hydrazide-hydrazones 5a-n were synthesized and evaluated for their cytotoxicity against selected human cancer cell lines. The reaction of indole-3-carboxaldehyde 2 with indole-3-carbohydrazide 4 in presence of catalytic amount of acetic acid afforded 5a-n in good yields. Among the synthesized bis(indolyl)hydrazide-hydrazones, the compound 5b with N-(p-chlorobenzyl) and bromo substituents was found to be the most potent against multiple cancer cell lines (IC(50)=1.0 μM, MDA-MB-231). The compound 5k exhibited selective cytotoxicity against breast cancer cell line MCF7 (IC(50)=3.1 μM).

Synthesis and in-vitro anticancer activity of 3,5-bis(indolyl)-1,2,4-thiadiazoles.

A series of 3,5-bis(indolyl)-1,2,4-thiadiazoles were synthesized and evaluated for their cytotoxicity against selected human cancer cell lines. The reaction of indole-3-thiocarboxamide 3 with iodobenzene diacetate underwent oxidative dimerization to give 3,5-bis(indolyl)-1,2,4-thiadiazoles 4a-n. Among the synthesized bis(indoly)-1,2,4-thiadiazoles, the compound 4h with 4-chlorobenzyl and methoxy substituents showed the most potent activity.

Synthesis and identification of α-cyano bis(indolyl)chalcones as novel anticancer agents.

Microwave-assisted synthesis of 23 α-cyano bis(indolyl)chalcones (6a-w) and their in vitro anticancer activity against three human cancer cell lines have been discussed. Among the synthesized chalcones, compound 6n was found to be the most potent and selective against A549 lung cancer cell line (IC50 = 0.8 μM). In a preliminary mechanism of action studies some α-cyano bis(indolyl)chalcones were found to enhance tubulin polymerization suggesting these compounds could act as microtubule stabilizing agents.

NMK-TD-100, a Novel Microtubule Modulating Agent, Blocks Mitosis and Induces Apoptosis in HeLa Cells by Binding to Tubulin

Thiadiazoles are one of the most widely utilized agents in medicinal chemistry, having a wide range of pharmacologic activity. Microtubules (MTs) have always remained a sought-after target in rapidly proliferating cancer cells. We screened for the growth inhibitory effect of synthetic 5-(3-indolyl)-2-substituted-1,3,4-thiadiazoles on cancer cells and identified NMK-TD-100, as the most potent agent. Cell viability experiments using human cervical carcinoma cell line (HeLa cells) indicated that the IC50 value was 1.42±0.11 µM for NMK-TD-100 for 48 h treatment. In further study, we examined the mode of interaction of NMK-TD-100 with tubulin and unraveled the cellular mechanism responsible for its anti-tumor activity. NMK-TD-100 induced arrest in mitotic phase of cell cycle, caused decline in mitochondrial membrane potential and induced apoptosis in HeLa cells. Immunofluorescence studies using an anti-α-tubulin antibody showed a significant depolymerization of the interphase microtubule network and spindle microtubule in HeLa cells in a concentration-dependent manner. However, the cytotoxicity of NMK-TD-100 towards human peripheral blood mononuclear cells (PBMC) was lower compared to that in cancer cells. Polymerization of tissue purified tubulin into microtubules was inhibited by NMK-TD-100 with an IC50 value of 17.5±0.35 µM. The binding of NMK-TD-100 with tubulin was studied using NMK-TD-100 fluorescence enhancement and intrinsic tryptophan fluorescence of tubulin. The stoichiometry of NMK-TD-100 binding to tubulin is 1:1 (molar ratio) with a dissociation constant of ~1 µM. Fluorescence spectroscopic and molecular modeling data showed that NMK-TD-100 binds to tubulin at a site which is very near to the colchicine binding site. The binding of NMK-TD-100 to tubulin was estimated to be ~10 times faster than that of colchicine. The results indicated that NMK-TD-100 exerted anti-proliferative activity by disrupting microtubule functions through tubulin binding and provided insights into its potential of being a chemotherapeutic agent.

Development of Novel Bis(indolyl)-hydrazide–Hydrazone Derivatives as Potent Microtubule-Targeting Cytotoxic Agents against A549 Lung Cancer Cells

The biological significance of microtubules makes them a validated target of cancer therapy. In this study, we have utilized indole, an important pharmacological scaffold, to synthesize novel bis(indolyl)-hydrazide-hydrazone derivatives (NMK-BH compounds) and recognized NMK-BH3 as the most effective one in inhibiting A549 cell proliferation and assembly of tissue-purified tubulin. Cell viability experiments showed that NMK-BH3 inhibited proliferation of human lung adenocarcinoma (A549) cells, normal human lung fibroblasts (WI38) and peripheral blood mononuclear cells (PBMC) with IC50 values of ∼2, 48.5, and 62 μM, respectively. Thus, the relatively high cytotoxicity of NMK-BH3 toward lung carcinoma (A549) cells over normal lung fibroblasts (WI38) and PBMC confers a therapeutic advantage of reduced host toxicity. Flow cytometry, Western blot, and immunofluorescence studies in the A549 cell line revealed that NMK-BH3 induced G2/M arrest, mitochondrial depolarization, and apoptosis by depolymerizing the cellular interphase and spindle microtubules. Consistent with these observations, study in cell free system revealed that NMK-BH3 inhibited the microtubule assembly with an IC50 value of ∼7.5 μM. The tubulin-ligand interaction study using fluorescence spectroscopy indicated that NMK-BH3 exhibited strong and specific tubulin binding with a dissociation constant of ∼1.4 μM at a single site, very close to colchicine site, on β-tubulin. Collectively, these findings explore the cytotoxic potential of NMK-BH3 by targeting the microtubules and inspire its development as a potential candidate for lung cancer chemotherapy.

A Facile Synthesis of Novel Bis‐(indolyl)‐1,3,4‐oxadiazoles as Potent Cytotoxic Agents

A recipe for potency: A novel series of bis(indolyl)-1,3,4-oxadiazoles was prepared from the corresponding hydrazide-hydrazones via iodobenzene diacetate-promoted oxidative cyclization. Evaluation against a panel of human cancer cell lines revealed that some derivatives possess potent cytotoxicity with tunable selectivity for different cancer types.

Organohypervalent Iodine Reagents in the Synthesis of Bioactive Heterocycles

Facile and metal-free syntheses of natural and natural product-inspired bioactive heterocycles are of paramount importance in drug discovery program; therefore, it is highly desirable to develop efficient protocols to generate a diverse library of drug-like molecules. In recent years, organohypervalent iodines have played a vital role as eco-friendly recyclable reagents to construct a variety of bioactive heterocycles, particularly with five- and six-membered ring systems. Due to readily accessible, easy-to-use and shorter reaction times, organohypervalent iodine reagents have gained special attention as versatile and benign oxidants in several organic transformations. Moreover, in a multistep synthesis of natural bioactive heterocycles, organohypervalent iodine reagents are important source to achieve key intermediates for being safer alternatives to hazardous and metal-based reagents. This chapter summarizes the recent trends adapted by organic chemists mainly in the synthesis of biologically relevant five- and six-membered heterocycles using such diverse organohypervalent iodine reagents.