Title : Thiadiazine-2-thione derivatives as new cell- cycle inhibitors
Abstract:
Cellular growth, development, and differentiation are tightly controlled by a conserved biological mechanism: the cell cycle. Deregulation of the cell cycle is a hallmark of the transformation of normal cells into tumor cells. Given its importance in tumorigenesis, several cell cycle inhibitors have emerged as potential therapeutic drugs for the treatment of cancers-both as single-agent therapy and in combination with traditional cytotoxic or molecular targeting agents. In recent years, the 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione scaffold have found many biological applications including antiproliferative activity. Accordingly, two series, a and b, of 3-cyclopentyl or (3-cyclohexyl)-5-substituted-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTT) 2a-9a and 3b, 4b, 6b-9b, were synthesized to develop new cell cycle inhibitors. Variable and promising in vitro antiproliferative activities were shown with the synthesized THTT derivatives. Compound 5a with a 5-cyclopentyl group on position-3 and a glutamine residue on position-5 of the THTT moiety showed maximum activity (IC50= 8.98 μM). Compound 5a possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. In addition, a pharmacophore-based study was performed to explain the biological activity on structural bases. A successful model was generated with a good correlation with the observed activity.
Audience Take Away Notes:
- Potential of Structure-based drug design for drug discovery and development
- Opening the windows for global scientific collaborations
- Improvement of the accuracy of drug design and providing new information to assist in solving drug design problems
- Searching for new leads to overcome of a global disaster
