New lipophilic phthalimido- and 3-phenoxybenzyl sulfonates: inhibition of antigen 85C mycolyltransferase activity and cytotoxicity.
Four new sulfonates were prepared as potential inhibitors of antigen 85C, a mycolyl transferase involved in the biosynthesis of the mycobacterial cell wall being designed on the basis of the proposed catalytic mechanism and antigen 85C crystal structure. The inhibitors contained a sulfonate moiety, 3-phenoxybenzyl alcohol or N-(hydroxyethyl)phthalimide as trehalose mimetics, and an alkyl chain of different length mimicking either the mycolate (alpha-chain or the mycolic acid (beta-branch. One compound displayed promising activity in a mycolyltransferase inhibition assay (compound 2b, IC50 = 4.3 microM). The two compounds containing a phthalimide moiety (compounds 3a and 3b) showed significant and selective cytotoxicity against the breast cancer cell line MDA-MB231.
Kovac
Andreja
A
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Wilson
Rosalind A
RA
Besra
Gurdyal S
GS
Filipic
Metka
M
Kikelj
Danijel
D
Gobec
Stanislav
S
D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000941:Antigens / Q000737:chemistry; D000942:Antigens, Bacterial / Q000737:chemistry*; D000995:Antitubercular Agents / Q000494:pharmacology*; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D009171:Mycolic Acids / Q000737:chemistry; D013451:Sulfonic Acids / Q000737:chemistry
D000941:Antigens; D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009171:Mycolic Acids; D013451:Sulfonic Acids; D000217:Acyltransferases; C119774:antigen 85C, Mycobacterium tuberculosis; C053820:trehalose mycolyltransferase