Synthesis, Electrochemistry, and Bioactivity of the Cyanobacterial Calothrixins and Related Quinones

Abstract

The calothrixins are quinone-based natural products isolated from Calothrix cyanobacteria which show potent antiproliferative properties against several cancer cell lines. Preliminary mechanistic studies suggest that the biological mode of action of the calothrixins may be linked to their ability to undergo redox cycling. In this study we compare the bioactivities of the calothrixins with those of structurally related quinones in order to identify the structural features in the calothrixins essential for biological activity. In particular, the reduction potentials of the calothrixins and some related quinones were measured electrochemically. Our studies indicate that while there is no direct correlation between the reduction potentials and biological activities of the studied compounds, in all cases quinones with EC(50) values <1.6 microM undergo reduction to their respective semiquinones readily, with their E(1/2) values being more positive than -0.5 V versus the standard hydrogen electrode (SHE).

Structure–activity delineation of quinones related to the biologically active Calothrixin B

“…Ellipticine quinone (22) was reported to have an EC 50 value of 0.15 lM against the HeLa cell lines. 10 The observed EC 50 value for isoquinolinedione (12) is 80-fold less than this, supporting the importance of rings A-C in the biological activity against HeLa cell lines. Similarly, the absence of the nitrogen atom in the D-ring (indolophenanthrene 7 versus Calothrixin 6) resulted in a drop in the potency observed.…”

“…(12) 12 ± 1 9 ± 2 >50 a In a previous study with HeLa cells, the EC 50 for benzocarbazoledione was found to be 0.43 ± 0.1 lM. 10 the different cell lines also highlight its specific utility against HeLa cells. With respect to P388 cells, only murrayaquinone A shows desirable selectivity.…”

“…This is consistent with the previously reported observations with benzocarbazoledione and ellipticine quinone (22). 10 These trends, however, were not observed with the P388 and CV-1 cell lines. It is interesting to note the 2-fold difference in the EC 50 values of the two regioisomers, murrayaquinone A (10) and 2-methylcarbazoledione (11).…”

“…In an earlier study, we reported that there was no direct correlation between the antiproliferative activity of the Calothrixins and related carbazolediones on HeLa cells, and the reduction potentials of these quinones. 10 As part of our ongoing studies to elucidate the structural requirements for the biological activity of these compounds, several simple quinone analogues of Calothrixin B were synthesized. These quinones were chosen to probe the importance of the rings A-E of Calothrixin B.…”

Palladium mediated intramolecular multiple C–X/C–H cross coupling and C–H activation: synthesis of carbazole alkaloids calothrixin B and murrayaquinone A

“…The pentacyclic carbazole alkaloids calothrixin A (1) and B (2) were isolated by Rickards et al from Calothrix cyanobacteria in 1999. 1 Calothrixins possess an unprecedented indolo[3,2-j]-phenanthridine framework with a striking assemblage of quinoline, quinone and indole pharmacophores.…”