Latrunculin A and Its C-17-O-Carbamates Inhibit Prostate Tumor Cell Invasion and HIF-1 Activation in Breast Tumor Cells

Latrunculin A (1) and B are macrolides reported by Kashman and coworkers from the Red Sea sponge Negombata magnifica Kelly-Borges and Vacelet (Podospongiidae).1 Latrunculins are reported to decrease intraocular pressure and increase outflow facility without corneal effects in monkeys.2,3 Latrunculin B and analogs showed antiangiogenic, antimetastatic, and antimicrobial activities.4 The most important biological effects of latrunculins are their abilities to disrupt microfilament organization and inhibit microfilament-mediated processes without affecting the organization of the microtubular system.5 The latrunculins bind reversibly to the cytoskeleton actin monomers, forming 1:1 complexes with G-actin and disrupting polymerization.5 Actin-active agents are attracting more attention in the field of cancer chemotherapy because microfilament and microtubule proteins form versatile dynamic polymers that can define cell polarity, organize cytoplasmic organelles, control cell shape and promote stable cell-cell and cell-matrix adhesions, and generate protrusive forces required for migration.6–8 These functions usually fail and become abnormal in cancer cells. 6–8 Based on X-ray crystallography, the binding site of 1 has been located between subdomains II and IV, in the vicinity of the ATP binding cleft of the protein target in the actin monomer.9,10 The binding pharmacophores of 1 to G-actin were identified as follows: C-1 carbonyl oxygen through water to glutamate 214 carboxy, C-17 lactol hydroxyl to arginine 210 NH (major binding), C-17 pyran oxygen to tyrosine 69 hydroxy, thiazolidinone NH to aspartate 157 carboxy, and thiazolidinone C-20 carbonyl oxygen to threonine 186 hydroxy.9,10 Only the thiazolidinone NH group acts as a hydrogen bonding donor while the rest of the binding functions act as hydrogen bonding acceptors.9,10 Semi-synthetic carbamoylation products of the C-17 lactol group in 1 were produced to study the pharmacological effects of the addition of hydrogen bond donors and acceptors at this key position. This study reports the anti-invasive and HIF-1 inhibitory activities of latrunculin A (1) and its semi-synthetic analogs (2–6).