Identification of novel CA IX inhibitor: Pharmacophore modeling, docking, DFT, and dynamic simulation.

Human Carbonic anhydrase IX (hCA IX) is found to be an essential biomarker for the treatment of hypoxic tumors in both the early and metastatic stages of cancer. Due to its active function in maintaining pH levels and overexpression in hypoxic conditions, hCA IX inhibitors can be a potential candidate specifically designed to target cancer development at various stages. In search of selective hCA IX inhibitors, we developed a pharmacophore model from the existing natural product inhibitors with IC50 values less than 50 nm. The identified hit molecules were then investigated on protein-ligand interactions using molecular docking experiments followed by molecular dynamics simulations. Among the zinc database 186 hits with an RMSD value less than 1 were obtained, indicating good contact with key residues HIS94, HIS96, HIS119, THR199, and ZN301 required for optimum activity. The top three compounds were subjected to molecular dynamics simulations for 100 ns to know the protein-ligand complex stability. Based on the obtained MD simulation results, binding free energies are calculated. Density Functional Theory (DFT) studies confirmed the energy variation between the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO). The current study has led to the discovery of lead compounds that show considerable promise as hCA IX inhibitors and suggests that three compounds with special molecular features are more likely to be better-inhibiting hCA IX. Compound S35, characterized by a higher stability margin and a smaller energy gap in quantum studies, is an ideal candidate for selective inhibition of CA IX.

Acridone-based antitumor agents: a mini-review.

In the past decades, tricyclic acridone ring system has become one of the major research interests of the medicinal chemists due to the biological significance of this moiety in drug design and drug discovery. Acridone scaffold has substantial bio-potential since it possess crucial activities such as antibacterial, antimalarial, antiviral and anti-neoplastic. The diverse biological activity of acridone and its prospective in reversal of multi-drug resistance has attracted attention of medicinal chemists to explore this scaffold especially to treat multi-drug resistance in cancer. Considering this potential in this review we have summarized the synthesis and the antitumor activities of different acridone derived compounds reported from 2000 to 2014.

Synthesis of novel amides based on acridone scaffold with interesting antineoplastic activity.

In search of novel cytotoxic agents based on acridone scaffold, twenty five derivatives of acridone-2- carboxamide were synthesized and evaluated against a panel of eleven cancer cell lines by using MTT assay. Amides, A5 and A8 (IC50 = 0.3 µM) exhibited good cytotoxicity against MCF7. Compound A22 (IC50 = 4.3 µM) was found to be selectively cytotoxic against cancer cell line MCF7 and KB403. Particularly, promising cytotoxic activities were shown by amides A6 (IC50 = 0.7 µM), A16 (IC50 = 6.3 µM), A8 (IC50 = 0.9 µM ), A21 (IC50 = 1.3 µM), A5 (IC50 = 2.9 µM), A8 (IC50 = 2.8 µM), A14 (IC50 = 0.8 µM), A9 (IC50 = 0.8 µM) and A8 (IC50 = 0.4 µM) against cell lines; PA1, WRL68, CaCO2, TK-10, K-562, PC-3, HOP-92, ECV-304 and UACC-257, respectively. The favorable cytotoxic profile and non-toxicity towards normal human cells displayed by the derivative revealed their potential for further anticancer drug developments.

Synthesis and evaluation of novel marine bromopyrrole alkaloid-based hybrids as anticancer agents.

A series of twenty three novel hybrids of marine bromopyrrole alkaloids with chalcone, isoxazole and flavone structural features were synthesized and evaluated for in vitro anticancer activity by MTT assay against five human cancer cell lines. Among the synthesized chalcones, hybrids 4a and 4h (IC50 range: 0.18 µM-12.00 µM) showed anticancer activity against all the tested cancer cell lines. Promising cytotoxic activities were exhibited by flavones derivatives, 5a and 5b (0.41 µM-1.28 µM) against cell lines PA1 and KB403. Isoxazole hybrids, 6b-6e selectively inhibited oral and mouth cancer cell line KB403, among which 6c (IC50 = 2.45 µM) was found to be most active.