Calothrixin

In 1999, Rickards et al. reported the isolation of calothrixins A (377) and B (378) from photoautrophic cultures of Calothrix cyanobacteria (345). These two, novel, pentacyclic carbazole alkaloids contain a quinolino[4,3-fc]carbazole-l,4-quinone framework. Calothrixins A and B inhibit the growth of a chloroquin-resistant strain of the malaria parasite P. falciparum and human HeLa cancer cells (345). 

The UV spectrum (/Imax 283, 352, and 405 nm) of calothrixin B (378) was similar to that of calothrixin A (377) indicating the presence of a similar pentacyclic quinolino[4,3- z]carbazole-l,4-quinone chromophore. Close comparison of the HREIMS of calothrixin B (378) with that of calothrixin A (377) indicated that... 

So far this class of carbazole alkaloids contains only two natural products, calothrixin A and its N-deoxy-derivative calothrixin B. These two pentacyclic metabolites with a quinolino[4,3- 7]carbazole-l,4-quinone framework displayed potent inhibitory effects on the in vitro growth of both human malarial parasites and human cancer cells and inhibition of RNA polymerase activity. Owing to this pharmaceutical potential, these natural products have attracted the synthetic interest of various research groups (8). 

Bennasar et al. reported a new radical-based route for the synthesis of calothrixin B (378) (869). This synthesis starts from the 2,3-disubstituted N-Boc indole 1558 and uses a regioselective intramolecular acylation of a quinoline ring as the key step for the construction of the calothrixin pentacyclic framework. Chemoselective reaction of in s/fM-generated 3-lithio-2-bromoquinoline [from 2-bromoquinoline 1559 with LDA] with the 3-formylindole 1558 followed by triethylsilane reduction of the... 

Recently, Moody et al. reported a biomimetic synthesis of calothrixin B (378) by oxidation of Hibino s 6-formylindole[2,3-fl]carbazole 1555 (870). The key intermediate 6-formyl-indole[2,3-fl]carbazole was readily obtained in six steps from indigo (1458). Using Somei s procedure, indigo (1458) was transformed to the cis-chlorohydrin 1461 in three steps and 50% overall yield (see Scheme 5.247). The reduction of the chlorohydiin 1461 gave 5-hydroxy-indolo[2,3-fl]carbazole 1564, and subsequent Vilsmeier formylation delivered the desired 6-formyl-indole[2,3-fl]carba-zole 1565 in 45% yield. Reaction of hydroxy-indolocarbazole 1565 with an excess of chloromethyl methyl ether (MOMCI) afforded the tiis-MOM-protected compound 1555. Following Hibino s approach, the tris-MOM-protected indolocarbazole 1555... 

The main framework is made up of five key modules for chemical library editing, enumeration, conversion, visualization, and analysis. The operations of these functionalities are accomplished by the various applications at the resource layer. For the purpose of illustration, the compound calothrixin B, a secondary metabolite isolated from the Calothrix cyanobacteria (11-13), is used as the scaffold molecule with the variable functional groups Rw] attached (Fig. 18.1). The calothrixins are redox-active natural products which display potent antimalarial and anticancer properties and thus there is interest in probing the physical as well as biological profiles of their derivatives (14). In this exercise, six functional groups have been selected as the building blocks (Table 18.1). 

Rickards, R. W., Rothschild, J. M., Willis, A. C., de Chazal, N. M., Kirk, J., Kirk, K., Sal-iba, K. J., Smith, G. D. (1999) Calothrixins A and B, novel pentacyclic metabolites from Calothrix Cyanobacteria with potent activity against malaria parasites and human cancer cells. Tetrahedron Lett 55, 13513-13520. 

Bernardo, P. H., Chai, C. L. L., Le Guen, M.,Geoffrey D., Smith, G. D., Waring, P. (2006) Structure-activity delineation of quinones related to the biologically active Calothrixin B. Bioorg Med Chem Lett 17, 82-85. 

Preliminary work with model selenoester 54 revealed that the hexabutyldistannane protocol, previously used in the phenyl and pyridine series, now gave poor yields of cyclized products. However, treatment of 54 under reductive TTMSS conditions in the presence of AIBN as the initiator led to the calothrixin-related pentacycle 55 in 65% yield. This compound, which incorporated the 2-cyano-2-propyl moiety of the initiator, was converted into A -methylcalothiixin 56 by treatment with potassium hydroxide in methanol, through a process involving a gramine-type nucleophilic substitution and the oxidation of the resulting carbinol by air. 

The reductive cyclization protocol was then applied to a suitably A-protected radical precursor to allow further access to the alkaloid calothrixin B. Satisfactorily, 2-indolylacyl radicals derived from A-(methoxymethyl) selenoester 57 underwent cyclization under TTMSS-AIBN conditions with an even higher efficiency than their A-methyl counterparts. The reaction nevertheless followed a different course as, after the radical addition and quinoline rearomatization, pentacyclic phenol 58, a fully aromatic tautomeric form of ketone P, was isolated in 90% yield. The same phenol 58 was isolated although in lower yields (50-70%) using either stannane-AIBN or AIBN-irradiation protocols. 

Bennasar M-L, Roca T, Ferrando F (2006) A new radical-based route to calothrixin B. Org Lett 8 561-564... 

Choshi, T, and Hibino, S. (2009) Progress towards the total synthesis of the bioactive calothrixins A and B. Heterocycles, T7, 85-97. 

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