Medicinal Chemistry

We identified two chiral chalcone analogs CCL360 and CCL361 from the Chiba Chemical Library, which exhibit antiproliferative effects on human cancer cells. Flow cytometry analyses revealed that HeLa and Vero cells treated with CCL360 and CCL361 had higher populations of cells in the G₂/M phase than untreated cells. Docking studies suggested that the R-isomer of CCL361 binds to the taxol binding domain (TBD) of β-tubulin, and the S-isomers of CCL360 and CCL361 bind to β-tubulin at the colchicine binding domain and the TBD. Further investigations using a fluorescent ubiquitination-based cell cycle indicator system revealed that the two compounds caused cell cycle arrest (in the M phase) and apoptosis only in HeLa cells. In non-cancerous Vero cells, however, CCL360 and CCL361 prolonged the G₂/M phase without causing apoptosis. Although increased expression levels of p53 and p21 were observed in all CCL360/361-treated cells, only HeLa cells exhibited increased levels of cleaved poly (ADP-ribose) polymerases and apoptosis. Increases in G₂/M phase populations in CCL360/361-treated cells are likely caused by increases in p-histone H3 (at Ser10) and Cyclin B1 levels. Furthermore, CCL360/361-treated HeLa cells exhibited phosphorylation of p-Plk1 (at Thr210) and dephosphorylation of p-Cdc2 (at Tyr15); these changes were not evident in CCL360/361-treated Vero cells, suggesting that the link between p53 and Plk1 in HeLa cells was likely compromised. Our study indicates that CCL360 and CCL361 are microtubule-targeting agents that can be used as lead compounds for developing novel anticancer drugs.

Some derivatives of benzene-sulphonamides were synthesized via condensation reaction. Pharmacokinetic parameters were evaluated to assess the oral bioavailability, permeability and transport properties of the compounds. Molecular docking studies were performed on farnesyl diphosphate synthase, pteridine reductase, ornithine decarboxylase and rhodesain to assess the potential of the reported compounds in treating human African trypanosomiasis. All the compounds showed good binding to the target proteins assayed.

Most of the diseases are multifactorial in nature. Moreover, the exploration of new drugs with appropriate absorption, distribution, metabolism, and excretion along with effective pharmacological activity and less toxicity for the treatment and cure of multifactorial diseases is a herculean task. There is new hope for the treatment of multifactorial diseases like cancer in recent years with the advent of Molecular hybridization. It is one of the approaches in the molecular modification of drug designing which involves the refinement of molecules. Chemists had learned well from nature about the significance of small changes in structures of drugs and its effect on biological activity. Molecular modification by nature has been going on since the beginning of life. Molecular hybridization is based on the combination of pharmacophores of different bioactive substances to produce a hybrid compound with improved affinity and efficacy when compared to the parent drugs. This strategy results in compounds with a modified selectivity profile, with different and/or dual modes of action and reduced undesired side effects. This technique focuses on the modulation of the pharmacophores giving rise to innovative hybrids. Molecular hybridization is a cropping up approach in drug discovery and development of medicinal chemistry during the latest years. The review article presents insights into the concept of molecular hybridization in designing better drugs.