Development of Benzimidazole-Substituted Spirocyclopropyl Oxindole Derivatives as Cytotoxic Agents: Tubulin Polymerization Inhibition and Apoptosis Inducing Studies.

A series of spirocyclopropyl oxindoles with benzimidazole substitutions was synthesized and tested for their cytotoxicity against selected human cancer cells. Most of the molecules exhibited significant antiproliferative activity with compound 12 p being the most potent. It exhibited significant cytotoxicity against MCF-7 breast cancer cells (IC50 value 3.14±0.50 µM), evidenced by the decrease in viable cells and increased apoptotic features during phase contrast microscopy, such as AO/EB, DAPI and DCFDA staining studies. Compound 12 p also inhibited cell migration in wound healing assay. Anticancer potential of 12 p was proved by the inhibition of tubulin polymerization with IC50 of 5.64±0.15 µM. These results imply the potential of benzimidazole substituted spirocyclopropyl oxindoles, notably 12 p, as cytotoxic agent for the treatment of breast cancer.

Regioselective synthesis and in vitro cytotoxicity evaluation of 3-thiooxindole derivatives: Tubulin polymerization inhibition and apoptosis inducing studies.

Herein, regiospecific nucleophilic ring-opening of spiroaziridine oxindoles has been established to afford 3-substituted-thiooxindole derivatives as anticancer agents. Among the new series, compounds 7d and 9c exhibited promising cytotoxic activity toward HCT-116 cells with IC50 values of 6.73 ± 0.36 and 6.64 ± 0.95 µM, respectively. Further, AO/EB, DCFDA, and DAPI staining studies were executed to establish the underlying apoptosis mechanism which displayed significant nuclear and morphological alterations. JC-1 staining and annexin V binding assay inferred the loss of mitochondrial membrane potential in HCT-116 cancer cells. Cell cycle analysis showed the treatment of 9c against HCT-116 cells, arrested the cell cycle in G2-M phase. In addition, tubulin binding assay revealed that compound 9c exhibited tubulin polymerase inhibition with IC50 value of 9.73 ± 0.18 µM. This inhibition of tubulin polymerase was further supported by binding interactions of 9c with tubulin through docking studies on PDB ID: 3E22.

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.

An update on the progress of cycloaddition reactions of 3-methyleneindolinones in the past decade: versatile approaches to spirooxindoles.

Cycloaddition reactions are of great interest due to their potential and rapid construction of optically enriched spiro-cyclic products. 3-Methyleneindolinones have been proven to be a valuable precursor in cycloaddition reactions for the construction of diverse 3,3'-spirocyclic oxindoles. Their versatile reactivity has provided a new forum for the development of a variety of building blocks and synthetic compounds, including bioactive molecules. Herein, significant accomplishments in the cycloaddition reactions of 3-methyleneindolinones for the synthesis of spirooxindoles have been summarised and elaborated. The review is outlined according to the type of cycloaddition such as [2 + 1], [2 + 2], [3 + 2], [4 + 2] and [5 + 2] cycloaddition reactions.

Structural insights of oxindole based kinase inhibitors as anticancer agents: Recent advances.

Small-molecule kinase inhibitors are being continuously explored as new anticancer therapeutics. Kinases are the phosphorylating enzymes which regulate numerous cellular functions such as proliferation, differentiation, migration, metabolism, and angiogenesis by activating several signalling pathways. Kinases have also been frequently found to be deregulated and overexpressed in cancerous tissues. Therefore, modulating the kinase activity by employing small molecules has emerged as a strategic approach for cancer treatment. On the other hand, oxindole motifs have surfaced as privileged scaffolds with significant multi-kinase inhibitory activity. The present review summarises recent advances in the development of oxindole based kinase inhibitors. The role of distinguished structural frameworks of oxindoles, such as 3-alkenyl oxindoles, spirooxindoles, 3-iminooxindoles and similar hydrazone derivatives have been described based on their kinase inhibition potential. Furthermore, the design strategies, mechanism of actions, structure activity relationships (SARs) and their mode of interaction with target protein have been critically highlighted.

TCCA-mediated oxidative rearrangement of tetrahydro-ß-carbolines: facile access to spirooxindoles and the total synthesis of (±)-coerulescine and (±)-horsfiline.

Multi-reactive centered reagents are beneficial in chemical synthesis due to their advantage of minimal material utilization and formation of less by-products. Trichloroisocyanuric acid (TCCA), a reagent with three reactive centers, was employed in the synthesis of spirooxindoles through the oxidative rearrangement of various N-protected tetrahydro-ß-carbolines. In this protocol, low equivalents of TCCA were required to access spirooxindoles (up to 99% yield) with a wide substrate scope. Furthermore, the applicability and robustness of this protocol were proven for the gram-scale total synthesis of natural alkaloids such as (±)-coerulescine (1) and (±)-horsfiline (2) in excellent yields.

An insight into medicinal attributes of dithiocarbamates: Bird's eye view.

Dithiocarbamates are considered as an important motif owing to its extensive biological applications in medicinal chemistry. The synthesis of this framework can easily be achieved via a one-pot reaction of primary/secondary amines, CS2, and alkyl halides under catalyst-free conditions or sometimes in the presence of a base. By virtue of its colossal pharmacological scope, it has been an evolving subject of interest for many researchers around the world. The present review aims to highlight various synthetic approaches for dithiocarbamates with the major emphasis on medicinal attributes of these architectures as leads in the drug discovery of small molecules such as HDAC inhibitor, lysine-specific demethylase 1 (LSD1) down-regulator, kinase inhibitor (focal adhesion kinase, pyruvate kinase, Bruton's tyrosine kinase), carbonic anhydrase inhibitor, DNA intercalators, and apoptosis-inducing agents. Moreover, recent medicinal advancements in the synthesis of dithiocarbamate derivatives as anticancer, antifungal, antibacterial, anti-Alzheimer, antitubercular, anti-glaucoma, anti-cholinergic, antihyperglycemic, anti-inflammatory activities have been elaborated with notable examples.

Syntheses and reactivity of spiro-epoxy/aziridine oxindole cores: developments in the past decade.

Spiro-epoxy/aziridine oxindole frameworks are considered as an efficient structural toolbox to obtain C3-functionalised oxindole derivatives. These 3,3'-spiro-cyclic precursors are highly susceptible towards nucleophiles owing to their inherent ring strain. Their versatile reactivity has opened many potential synthetic transformations, allowing access to bioactive molecules as well as natural products. The present review aims to elaborate various enabling strategies applied in the successful synthesis of strained spiro-cyclic oxindole scaffolds. Furthermore, the nucleophilic ring-opening/expansion and cycloaddition reactions of spiro-epoxy/aziridine oxindole are well discussed. Moreover, mechanistic insights to define the regio- and stereo-chemical outcome of the products have also been highlighted briefly.

Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect.

The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 µM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) cancer cell lines, respectively. All these compounds were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, 12d, 12e, 12k, 12l, 12p, 12q, 12t and 12u prominently suppressed VEGFR-2, with IC50 values of 310-920 nM in association to the positive control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by 12k in a dose-dependent manner. Molecular docking studies also shown that compound 12k capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.

Reliability of Click Chemistry on Drug Discovery: A Personal Account.

The unprecedented efficiency, reliability and adaptability in drug discovery, with the growing number of applications and impact, have made Click Chemistry fascinating to the scientific community. The specificity, biocompatibility along with other principles of click chemistry offers a reliable platform for the synthesis of drug-like molecules that can expedite the drug discovery process. This account summarizes such successes of versatile click reactions from our research group towards the development of functional molecules.