Dhanya Sunil

Some new indole–coumarin hybrids; Synthesis, anticancer and Bcl-2 docking studies

Hybrid molecules have attracted attention for their improved biological activity, selectivity and lesser side effects profile, distinct from their individual components. In the quest for novel anticancer drug entities, three series of indole-coumarin hybrids - 3-(1-benzyl-1H-indol-2-yl)-2H-chromen-2-ones, 2-(2-oxo-2H-chromen-3-yl)-1H-indole-3-carbaldehydes and 2-(2-oxo-2H-chromen-3-yl)-1H-indole-3-carboxylic acids were synthesized. All the synthesized compounds were characterized by spectral techniques like IR, (1)H NMR, (13)C NMR, mass spectrometry and elemental analysis. In silico docking studies of synthesized molecules with apoptosis related gene Bcl-2 that is recognized to play an important role in tumerogenesis were carried out. Dose-dependent cytotoxic effect of the compounds in human breast adenocarcinoma (MCF-7) and normal cell lines were assessed using MTT assay and compared with that of the standard marketed drug, Vincristine. Compound 4c had a highly lipophilic bromine substituent capable of forming halogen bond and was identified as a potent molecule both in docking as well as cytotoxicity studies. Flow cytometric cell cycle analysis of 4c exhibited apoptotic mode of cell death due to cell cycle arrest in G2/M phase. Structure activity relationship of these hybrid molecules was also studied to determine the effect of steric and electronic properties of the substituents on cell viability.

Indole Based Tubulin Polymerization Inhibitors: An Update On Recent Developments.

The exploration of cancer microenvironment and its physiology have exposed a number of potential molecular targets for selective therapeutic intervention by anti-cancer agents. Microtubules are basic cell components formed by polymerization of αβ heterodimers which play a pivotal role in cellular functions as well as cell division. Drugs that can control the microtubule assembly either by hindering tubulin polymerization or by obstructing microtubule disassembly are of great importance in anti-cancer therapy. Diverse classes of naturally occurring as well as synthetic and semi-synthetic compounds with an indole nucleus induce microtubule polymerization and depolymerization and thereby change tubulin dynamics. Rapid development of several novel tubulin polymerization inhibitors has been observed over the past few years and some of them have associated vascular disrupting properties too. The present review starts with the structure, function and importance of microtubules in a eukaryotic cell. The well characterized tubulin binding domains and the corresponding inhibitors including their mechanism of action is also a part of this article. The report mainly focuses on the brief synthetic methodology with the relevant SAR studies of different indole derived molecules that have been reported in the past few years as potential inhibitors of tubulin polymerization is discussed. This review will provide the up-to-date evidence-base for synthetic chemists as well as biologists to design and synthesize new active molecules to inhibit tubulin polymerization.

Nano-Chitosan Particles in Anticancer Drug Delivery: An Up-to-Date Review

BACKGROUND Cancer is one of the most awful lethal diseases all over the world and the success of its current chemotherapeutic treatment strategies is limited due to several associated drawbacks. The exploration of cancer cell physiology and its microenvironment has exposed the potential of various classes of nanocarriers to deliver anticancer chemotherapeutic agents at the tumor target site. These nanocarriers must evade the immune surveillance system and achieve target selectivity. Besides, they must gain access into the interior of cancerous cells, evade endosomal entrapment and discharge the drugs in a sustained manner. Chitosan, the second naturally abundant polysaccharide is a biocompatible, biodegradable and mucoadhesive cationic polymer which has been exploited extensively in the last few years in the effective delivery of anticancer chemotherapeutics to the target tumor cells. Therapeutic agent-loaded surface modified chitosan nanoparticles are established to be more stable, permeable and bioactive. CONCLUSION This review will provide an up-to-date evidence-based background on recent pharmaceutical advancements in the transformation of chitosan nanoparticles for smart anticancer therapeutic drug delivery. HIGHLIGHTS • Efforts to improve cancer chemotherapy by exploiting the intrinsic differences between normal and neoplastic cells to achieve maximum effective drug delivery to target cancer cells through bioengineered chitosan nano delivery vectors are discussed. • The easy manipulation of surface characteristics of chitosan based nanoparticles by various functionalization methods to achieve targeted drug delivery proves its potential to be an essential tool for the advancement of anticancer drug-delivery vectors.

Bisindole‐oxadiazole hybrids, T3P®‐mediated synthesis, and appraisal of their apoptotic, antimetastatic, and computational Bcl‐2 binding potential

Retraction: Kamath PR, Joseph MM, Ajees AA, et al. Bisindole‐oxadiazole hybrids, T3P mediated synthesis and appraisal of their apoptotic, antimetastatic and computational Bcl‐2 binding potential. J Biochem Mol Toxicol. 2017;31:e21962. https://doi.org/10.1002/jbt.21962

Oxazepine Derivative as an Antitumor Agent and Snail1 Inhibitor against Human Colorectal Adenocarcinoma

Colorectal cancer is the third most common malignancy in man, with significant morbidity and mortality. Metastasis, the major cause of cancer-associated deaths occurs as a multistep process, where cancer cells detach from the primary tumor, intravasate circulation to disseminate and invade surrounding tissues to form the secondary tumors. The effectiveness of many anticancer drugs is limited by their toxicity to normal rapidly growing cells. Four oxazepines were synthesized by the cycloaddition reaction between schiff bases and maleic anhydride, which were characterized by CHN analysis and advanced spectral techniques. The cytotoxicity of oxazepines against HCT116 (human colon cancer) cell lines were studied using Sulphorhodamine-B (SRB) assay, and their antimigratory properties using wound healing assay. 1-[2-(2,3-dihydro-1H-indol-3-yl)-4,7-dioxo-4,7-dihydro-1,3-oxazepin-3(2H)- yl]thiourea (2b) exhibited very low IC50 in SRB assay with good antimigratory activity as observed in wound healing assay. Snail 1, a transcription regulator of E-cadherin induces epithelial-to mesenchymal transition, reduces intercellular adhesion and increases cell motility, endows epithelial cancer cells with migration and invasive properties. Snail1 is upregulated in several human cancers and is frequently associated with apoptotic resistance, invasiveness, metastases and poor prognosis and it can act as a molecular target in cancer treatment. The docking studies of 2b with the active site of snail1 suggest it to be a potent chemotherapeutic agent in the treatment of colorectal cancer

2-Phenoxy-acetohydrazide.

In the title compound, C8H10N2O2, the acetohydrazide group is almost planar, with an r.m.s. deviation of 0.028 Å. In the crystal, the molecules are linked by intermolecular C—H⋯O, N—H⋯O and N—H⋯N hydrogen bonds into infinite sheets lying parallel to (001). The acetohydrazide O atom accepts two N—H⋯O links and one C—H⋯O link.

New oxadiazole derivatives: Synthesis and appraisal of their potential as antimicrobial agents

The escalating threat due to dwindling effect of antibiotics and challenge of tackling rising drug-resistant infections has gathered high focus in current medicinal research. Methods: In an attempt to find new molecules that can defeat microbial resistance, two new series of 2-[2-substituted ethenyl]-5-(substituted methoxy)-1,3,4-oxadiazole derivatives were synthesized. Various aromatic hydrazides were allowed to undergo cyclization to substituted oxadiazole-2- amines in the presence of cyanogen bromide and further condensed with different heterocyclic aldehydes to give new oxadiazole derivatives. The synthesized molecules were fully characterized by various spectral techniques and tested for antimicrobial activity. Results: Almost all the newly synthesized compounds especially (5g-5l) displayed remarkable growth inhibition against three bacterial strains: M. smegmatis, S. aureus, E. coli and fungi C. albicans. The antimicrobial activity was further confirmed by MIC assay against the same microorganisms. Oxadiazole 5g displayed promising activity with a MIC value of 0.025 mM for two bacteria and fungi, whereas MIC of this compound for E. coli was 0.1 mM. Other active compounds (5h-5l) also exhibited good MIC ranging between 0.313 to 5.0 mM against the selected microorganisms. Docking simulations were generated to explore the potential binding approaches of ligand 5g at the D-alanine:d-alanine ligase (Ddl) protein of E. coli and S. aureus. Conclusion: Molecule 5g was active even at a lower concentration and could probably act as a prospective lead molecule for targeting the drug resistant microorganisms.

Discovery of new inhibitors of CdC25B by structure-based docking studies

The cdc25 family of phosphatases plays a vital role in cell cycle regulation. The role of CdC25B (one of the isoforms of CdC25) in tumor cell growth is well recognized. All the active site of the CdC25 proteins has the consensus Cys-X5-Arg motif. Based on the three-dimensional structural studies, the role of the cysteine and arginine residues in CdC25B proteins are accurately established. Alteration of either the cysteine and arginine residues of the Cys-X5-Arg motif led to the loss of both reductase and phosphatase activities. R is a highly conserved arginine that hydrogen bonds to the phosphorylated amino acid of the substrate. Structural evidence suggests that the toxic metals like arsenic bind strongly to cysteine the carbonyl group of residue Cys477 in Ccd25B points toward the location where phosphate should bind. Recently Lund et al. [1] have identified two potential inhibitors for CdC25B (PDB ID: 4WH7, and 4WH9). Interestingly these small molecules [2fluoro-4-hydroxybenzonitrile and 2-[(2-cyano-3-fluoro-5-hydroxyphenyl) sulfanyl] ethanesulfonic acid] bound to a different pocket primarily comprised of Phe386, Leu398, Cys484, Arg488, and Met505 on CdC25B located approximately 15 Angstrom away from the Cys-X5-Arg active site. This alternative active site is relatively more polar and connects well with water hydrogen bonding network. Currently, we have proposed a set of 34 novel compounds, which may be the potential inhibitors for CdC25B. The molecular docking technique has been employed to identify the affinity of the molecules, and all the compounds were docked in all major active sites. The result suggest that 3‐[(pyridin‐4‐yl)methyl]‐3‐ azatricyclo[7.3.1.05,13] trideca‐1(12),5,7,9(13),10‐pentaene‐2,4‐dione&8‐bromo‐3‐[(pyridin‐4‐yl)methyl]‐3‐azatricyclo [7.3.1.05,13] trideca‐1(12),5,7,9(13),10‐pentaene‐2,4‐dione ) (-7.1 kcal/mol, -6.4 kcal/mol) has better affinity than the molecules identified by Lund et al. (-5.1kcal/mol) [1]. And these molecules also have better hydrogen bonding and hydrophobic interactions with several amino acids in the secondary active site. The proposed molecules docked at Cys-X5Arg active site, revealed some interesting protein interactions. In summary, we identified some novel high-affinity inhibitor molecules to block the activity of CdC25b phosphates, which may provide an opportunity to target this important class of proteins. [1] Lund G. et al.(2015).Acs Chem.Biol. 10: 390-394

2-(2-Chlorophenoxy)acetohydrazide

In the title compound, C8H9ClN2O2, the acetohydrazide group is approximately planar, with the maximum deviation of 0.031 (2) Å. In the crystal, the molecules are linked by N—H⋯N, N—H⋯O and C—H⋯O hydrogen bonds, with the acetohydrazide O atom accepting two C—H⋯O links and one N—H⋯O link. This results in infinite sheets lying parallel to (100).