Design of beta-lactams with mechanism based nonantibacterial activities.
The majority of nonantibacterial activities discovered for beta-lactam derivatives during the last 15 years are based on their ability to form a stable covalent complex with nucleophile in the active site of enzymes regulating fundamental physiological processes in mammalian organism such as serine and cysteine proteases, LDL phospholipase A(2), A-independent transacylase and some still indeciphered enzymes. Regulation of their catalytic activity both in vitro and in vivo by compounds designed on the cephalosporin, penicillin and 2-azetidinone base was successfully exploited in the treatment of inflammatory, respiratory, cardiovascular disorders, cancer and other pathologic processes. Availability of X-ray crystallographic data for target enzymes and computational molecular modelling in combination with wide possibilities of structural modifications for commercial natural and synthetic beta-lactams and the chiral blocks allow to consider this class of organic compounds as a perspective source of mechanism based nonantibacterial drugs.
Veinberg
Grigory
G
Latvian Institute of Organic Synthesis, 21 Aizkraukles Street, Riga, LV 1006, Latvia. veinberg@osi.lv
Vorona
Maxim
M
Shestakova
Irina
I
Kanepe
Iveta
I
Lukevics
Edmunds
E
D000217:Acyltransferases / Q000037:antagonists & inhibitors; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors; D047090:beta-Lactams / Q000737:chemistry* / Q000494:pharmacology
D000935:Antifungal Agents; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D047090:beta-Lactams; D000217:Acyltransferases; C039766:arachidonyl transacylase; D010741:Phospholipases A; D010196:Pancreatic Elastase; D013917:Thrombin; D017430:Prostate-Specific Antigen