Director: Professor Emeritus Dr. Somsak Ruchirawat

For some selected compounds already prepared on a lab-scale, the corresponding procedures appropriate for their scale-up to the pre-pilot (kilogram) levels have been carefully executed; this is highly critical to reflect the practicability of the developed protocols and serves as a bridge to further translate them from the laboratory to the industry. Selection of a synthetic route must accommodate methods of purification which, towards the industrial applications, involve either crystallization for solid or distillation for liquid with minimal, if any, column chromatography. Other equipment necessary for the separation of organic- and aqueous-soluble layers is also vital. Moreover, appropriate analytical instruments such as high-performance liquid chromatography (HPLC) to follow the progress of the reaction must accommodate the real-time analysis. During the COVID-19 pandemic, our laboratory has successfully upscaled the preparation of the anti-viral drug molnupiravir starting from cytidine. Two synthetic routes—one using only chemicals and the other using immobilized lipase—have been successfully executed to furnish the desired product in only 2-3 steps in comparable overall yields on the kilogram scales. Using enzyme as a biocatalyst also conforms to the Thai government policy on the bio-circular-green economy (BCG) for sustainable development. This is an important step forward to establish the requisite process chemistry in Thailand for producing APIs on larger scales.

Structure-activity relationships (SARs) are keys to the success of drug discovery and development programs as they provide the pivotal link between structural modifications and desirable biological activities. To this end, viable synthetic strategies must be robust and accommodate a wide range of functional group installations at various stages to generate libraries of candidates with sufficiently explored chemical spaces. Detailed molecular mechanisms of biological actions have been performed to shed some light on understanding the interactions between the molecular target and ligands. Similar to modern drug discovery programs, toxicological profiling has been integrated at an early stage to enhance the success rate of advancing these drug-like candidates to further stages of drug discovery and development process.

      The advent of hardware with powerful computing capability and software with multifaceted applications for chemistry has enabled the more accurate identification of the discrete stereo- and regio-chemical issues of plausible structures with greater certainty and efficiency. The process encompasses the spectroscopic data of the compounds in question and statistical analysis of the possible structures to delineate the true compound identity. In addition, relevant reaction coordinate parameters and experimentally obtained data (e.g., kinetic, physical as well as spectroscopic) can be utilized to distinguish plausible reaction pathways, thereby determining the reaction mechanism. Knowledge from computational chemistry can be utilized as a guide to design or improve the reactions which may deliver the desired products in higher yields, with better stereoselectivities, regioselectivities, and chemical selectivity.

Challenges in total synthesis of natural products lie in the disconnection and execution of series of chemical reactions. Ingenious insights and capability to exploit and manipulate available repertoire of chemical methods as well as subtle differences in chemical reactivities are crucial for the successfully designed synthetic approaches with highest efficiency. In addition, utility of biomimetic/bio-inspired syntheses has also been illustrated. Stereochemical outcomes of each step for those containing stereogenic centers are important considerations upon devising synthetic routes. Divergent synthesis has also played an important role in designing a synthetic strategy to a common intermediate for the preparation of other analogs, thus increasing the efficiency and flexibility of such developed route. State-of-the-art synthetic approaches for various cores of natural products have been designed and executed successfully. Over the years, our laboratory has prepared both plant- and marine-derived natural products and their analogs including: lamellarins/azalamellarins, (±)-palodesangrens, (±)-paucifloral F, negundin A, (+)-ζ-clausenamide, (+)-balasubramide, cannabinol, isocryptolepine, (±)crispine A, (+)-phenanthroindolizidine, (+)-phenanthroquinolizidine, (±)-seco-antofine, (±)-julandine, lophocladines, (±)-castanospermine, (+)-8-aminolentiginosine, and (-)-epi-epiquinamide.

Developing novel and efficient synthetic methods play vital roles in advancing organic synthesis to access privileged scaffolds. Not only has catalysis been a cornerstone for developing various methods and the protocols with less impact or footprint on the environment also deemed absolutely necessary for sustainability. Novel chemistries have been devised on the basis of green chemistry principles such as the use of water as a solvent, solid-supported chemicals as reagent, and microwave/electricity/light as alternative and renewable sources of energy. Modern practices on organic synthesis have been employed to the fullest potential, spanning from the chemo-, regio-, and stereo-selective processes to the cyclization of multi-ring systems. Annulation of different ring sizes as well as installation of chemically unique functional groups have been successfully achieved via these considerations. Developing these synthetic methods has enabled our laboratory to advance the frontier in organic synthesis to discover the untapped areas of research. New chemical reactivities of various reactive intermediates have been revealed, many of which are unprecedented. Transition-metal catalysis such as Pd, Pt, Ag, Ru, Cu, Ni, and Ir has been exploited to affect novel bond formations.

Name : Miss Bunkuea Chantrathonkul (Research Assistant) Office Address : Room : 1704 CGI Laboratory of Medicinal Chemistry 54 Kamphaeng Phet 6 Talat Bang Khen, Lak Si, Bangkok 10210, Thailand Tel : +66 2554 1900 (ext. 2727) Email : [email protected] Research Interests Biological activities Small molecule compounds Drug-like compounds Education 1995-1999 B.A. Apply Biology, Suan Sunandha Institute, Thanland Work Experiences 2004 – present Research Assistant, Chulabhorn Research Institute, Thailand Publications Selected Publications Sopha P, Phutubtim N, Chantrathonkul B, Ploypradith P, Ruchirawat S,Chittchang M. Roles of autophagy in relation to mitochondrial stress responses of HeLa cells to lamellarin cytotoxicity. Toxicology. 2021;462:152963. Other Publications Intaramat A, Sornprachum T, Chantrathonkul B, Chaisuriya P, Jongruja N, Kumsang Y, Sandee A, Santurio J, Grooters A, Ratanabanangkoon K. Protein A/G-based immunochromatographic test for serodiagnosis of pythiosis in human and animal subjects from Asia and Americas. Med Mycol. 2016;54(6):641-7. Ratanabanangkoon K*, Simsiriwong P, Pruksaphon K, Tan K, Eursakun S, Tan C, Chantrathonkul B, Wongwadhunyoo W, Youngchim S, Tan N. A novel in vitro potency assay of antisera against Thai Naja kaouthia based on nicotinic acetylcholine receptor binding. Sci Rep. 2017;7(1):8575. Ratanabanangkoon K*, Simsiriwong P, Pruksaphon K, Tan K, Chantrathonkul B, Eursakun S, Tan C. An in vitro potency assay using nicotinic acetylcholine receptor binding works well with antivenoms against Bungarus candidus and Naja naja. Sci Rep. 2018;8:9716.