Semisynthetic latrunculin B analogs: studies of actin docking support a proposed mechanism for latrunculin bioactivity.
Latrunculins are unique macrolides containing a thiazolidinone moiety. Latrunculins A, B and T and 16-epi-latrunculin B were isolated from the Red Sea sponge Negombata magnifica. N-Alkylated, O-methylated analogs of latrunculin B were synthesized and biological evaluation was performed for antifungal and antiprotozoal activity. The natural latrunculins showed significant bioactivity, while the semisynthetic analogs did not. Docking studies of these analogs into the X-ray crystal structure of G-actin showed that, in comparison with latrunculins A and B, N-alkylated latrunculins did not dock satisfactorily. This suggests that the analogs do not fit well into the active site of G-actin due to steric clashes and provides an explanation for the absence of bioactivity.
Department of Pharmacognosy, The University of Mississippi, University, MS 38677-1848, United States.
Sucheta
S
Kudrimoti
Safwat A
SA
Ahmed
Pankaj R
PR
Daga
Amir E
AE
Wahba
Sherief I
SI
Khalifa
Robert J
RJ
Doerksen
Mark T
MT
Hamann
D000199:Actins / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D011161:Porifera / Q000737:chemistry; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000199:Actins; D000935:Antifungal Agents; D000981:Antiprotozoal Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D053778:Thiazolidines; C037068:latrunculin B; C037067:latrunculin A