Latrunculin with a Highly Oxidized Thiazolidinone Ring:  Structure Assignment and Actin Docking

Abstract

A new latrunculin, oxalatrunculin B (3), was isolated from Red Sea sponge Negombata corticata. Extensive spectroscopic analysis revealed an unprecedented heterocycle in which the rare thiazolidinone ring found in latrunculins was oxidized with three additional oxygens. An actin polymerization inhibition assay agreed with MM-PBSA free energy calculations that 3 binds more weakly than latrunculin B to actin. Significant antifungal and anticancer activity of 3 was found, suggesting an alternate target in addition to actin for latrunculin bioactivity.Latrunculins A (1) and B (2) (Fig. 1) were first isolated from Negombata magnifica (Keller) (formerly Latrunculia magnifica), discovered from the Red Sea. 1 Among the characteristic features of these natural products is the presence of a macrocyclic lactone ring of 14 or 16 carbon atoms and a 2-thiazolidinone moiety (Figure 1). 2,3 In vitro experiments revealed that the latrunculins disrupt actin polymerization, 4 a possible target for cancer. 5A recent study has also reported antimigratory and antiangiogenic activity of latrunculins, adding to their possible utility in the control of cancer. 6 In addition to significant ichthyotoxic and cytotoxic properties, the latrunculins are also antiviral against herpes simplex type 1 virus (HSV-1). 7Several new latrunculins including natural, synthetic or semisynthetic analogs have been reported recently. 6,8 We report here the structure assignment and bioactivity of a unique new jkhalifa_99@yahoo.com, rjd@olemiss.edu, mthamann@olemiss.edu. As further evidence for this, combustion analysis on 3 showed 53.6% carbon, 6.51% hydrogen, 3.16% nitrogen, 28.6% oxygen and 6.34% sulfur. 13 C NMR indicated that the carbon skeleton of 3 consisted of 2 methyl carbons, 7 methylenes, 7 methines and 4 quaternary carbon atoms, which is identical to the carbon multiplicities of 2. The 13 C NMR chemical shifts for the 14-membered and tetrahydropyran rings were in close agreement with those of 2 revealing that additional oxygenation must occur at the heteroatoms. Significant differences were found in the chemical shifts of the thiazolidinone ring. The C-17 resonance shifted downfield from δ28.5 to δ49.9 indicating the introduction of a neighboring oxygen atom. C-16 shifted slightly upfield so the only possible position for oxidation was at the sulfur atom. C-18 also moved upfield from δ175.3 to δ157.3. The chemical shift of the carbonyl carbon of a 5-membered lactam ring will move upfield around 15ppm when the lactam nitrogen is hydroxylated. 9,10 It has also been shown that oxygenation of the sulfur atom adjacent to the carbonyl of a 5-membered thiazolidinone will move chemical shifts upfield by ~10 ppm. 11 This suggested that two of the three new oxygen atoms are at the S and the last is assigned as the hydroxyl group at N. Further evidence for this was the disappearance of the H-N at δ6.1. In addition the amide IR resonance in 2 is absent in 3 and a new resonance at 1756 cm −1 appeared, indicating the presence of a CONOH system. 11 The OH...

Migrastatics—Anti-metastatic and Anti-invasion Drugs: Promises and Challenges

“…The compound structure is a 14- or 16-membered macrolide base attached to a 2-thiazolidinone moiety [52]. Latrunculin A was found to inhibit the invasion of the tumorigenic AdoMetDC transformants of murine fibroblasts [53], the human breast cancer G3S1 cell line [54] and HeLa-O3 cells [55].…”

Bioactive heterocycles containing endocyclic N-hydroxy groups

“…Cytotoxicity of oxalatrunculin B against several cancer cell lines suggested that compound 32 displayed nonspecific cytotoxicity against solid tumor cells and hematopoietic cancerous cells, possessing MIC value of 16.3 μM against hepatocellular carcinoma. The weak binding to actin and the stronger cytotoxic activity suggest that may exist a secondary target responsible for the different activities of 32 [60]. Austin et al patented a series of N -hydroxy derivatives as industrial biocides.…”

Crystal structure of (2Z,5Z)-3-allyl-5-(4-(methylthio)benzylidene)- 2-(p-tolylimino)thiazolidin-4-one, C21H20N2OS2

“…Thiazolidinone moiety is an important structure element in medicinal chemistry [2][3][4][5][6] and substituted thiazolidinones show a broad spectrum of biological activities [7][8][9][10][11] [16].Therefore, facile preparation of various 5-arylidene thiazolidinones is highly desirable. In continuation of our ongoing interests in the development of benign methods targeted at the synthesis of biologically important heterocycles [17][18][19], we used base supported ionic liquid-like phase (SILLP) [20] as an efficientand recyclablesolid phasecatalystinthe synthesis of thetitle compound.…”

“…Thiazolidinone moiety is an important structure element in medicinal chemistry [2][3][4][5][6] and substituted thiazolidinones show a broad spectrum of biological activities [7][8][9][10][11]. In particular, 5-arylidene-4-thiazolidinones have been synthesized and employed as new agents with SHP-2 inhibitory action [12],aspotential antifungal and antibacterial drugs [13],asPTP1Band LMW-PTP inhibitors [14],a nti-inflammatory agent [15] and antimicrobial drugs [16].Therefore, facile preparation of various 5-arylidene thiazolidinones is highly desirable.…”