Cyanobacterial Metabolite Calothrixins: Recent Advances in Synthesis and Biological Evaluation

Abstract

The marine environment is host to unparalleled biological and chemical diversity, making it an attractive resource for the discovery of new therapeutics for a plethora of diseases. Compounds that are extracted from cyanobacteria are of special interest due to their unique structural scaffolds and capacity to produce potent pharmaceutical and biotechnological traits. Calothrixins A and B are two cyanobacterial metabolites with a structural assembly of quinoline, quinone, and indole pharmacophores. This review surveys recent advances in the synthesis and evaluation of the biological activities of calothrixins. Due to the low isolation yields from the marine source and the promise this scaffold holds for anticancer and antimicrobial drugs, organic and medicinal chemists around the world have embarked on developing efficient synthetic routes to produce calothrixins. Since the first review appeared in 2009, 11 novel syntheses of calothrixins have been published in the efforts to develop methods that contain fewer steps and higher-yielding reactions. Calothrixins have shown their potential as topoisomerase I poisons for their cytotoxicity in cancer. They have also been observed to target various aspects of RNA synthesis in bacteria. Further investigation into the exact mechanism for their bioactivity is still required for many of its analogs.

Keywords: anticancer activity; antimicrobial activity; calothrix; calothrixin; cyanobacteria; marine natural product; total synthesis.

Figure 1

Biologically active natural products isolated from marine cyanobacteria.

Figure 2

Structures of calothrixins.

Scheme 1

Velu’s synthesis of calothrixins.

Scheme 2

Ishikura’s synthesis of calothrixins.

Scheme 3

Dethe’s synthesis of calothrixin B.

Scheme 4

Nagarajan’s synthesis of calothrixin B.

Scheme 5

Mal’s synthesis of calothrixin B and its regioisomer.

Scheme 6

Kusurkar’s total synthesis of calothrixin B.

Scheme 7

Nagarajan’s synthesis of calothrixins A and B.

Scheme 8

Mohanakrishnan’s synthesis of calothrixins A and B.

Scheme 9

Kumar’s synthesis of calothrixins B.

Scheme 10

Alternate synthesis of compound 64.

Scheme 11

Hibino’s synthesis of calothrixin B.

Scheme 12

Mohanakrishnan’s synthesis of calothrixins B.