Thiadiazine-2-thione derivatives as new cell- cycle inhibitors

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 

Biography:

Prof. Tarek Aboul-Fadl has completed his PhD in Medicinal Chemistry from Assiut University, Egypt (1994) under the channel system and joint supervision scheme between Assiut University and Josai University/Japan. He performed his postdoctoral training as a postdoctoral research fellow and scientist of Pharmaceutical and Medicinal Chemistry at University of Vienna, Austria (1997- 1998), Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany (1999 and 2013) and University of Utah, USA (2001-2002 and 2004-2005).  He has over 77 publications and 4 patents that have been cited over 1880 times, and his publication H-index is 23(google_scholar).  He awarded ACDIMA Research Award for the Best Scientific Research in Arab World, 2012.