A new structural class of S-adenosylhomocysteine hydrolase inhibitors.
Effective inhibitors of S-adenosylhomocysteine hydrolase hold promise towards becoming useful therapeutic agents. Since most efforts have focused on the development of nucleoside analog inhibitors, issues regarding bioavailability and selectivity have been major challenges. Considering the marine sponge metabolite ilimaquinone was found to be a competitive inhibitor of S-adenosylhomocysteine hydrolase, new opportunities for developing selective new inhibitors of this enzyme have become available. Based on the activities of various hybrid analogs, SAR studies, pharmacophore modeling, and computer docking studies have lead to a predictive understanding of ilimaquinone's S-adenosylhomocysteine hydrolase inhibitory activities. These studies have allowed for the design and preparation of simplified structural variants possessing new furanoside bioisosteres with 100-fold greater inhibitory activities than that of the natural product.
Kim
Byung Gyu
BG
Merkert Chemistry Center, Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.
Chun
Tae Gyu
TG
Lee
Hee-Yoon
HY
Snapper
Marc L
ML
D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011809:Quinones / Q000737:chemistry* / Q000494:pharmacology*; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D011809:Quinones; D012717:Sesquiterpenes; C467077:ilimaquinone; D012435:S-Adenosylhomocysteine; D043383:Adenosylhomocysteinase