Diterpenoids aphidicolin

Biosynthesis of the diterpenoid aphidicolin. Isolation of intermediates from P450 inhibitor treated mycelia of Phoma betae, H. Oikawa, S. Ohashi, A. Ichihara and S. Sakamura, Tetrahedron, 1999, 55, 7541. 

A soln. of 110 mg 3a,5a-dihydroxyandrostane in dimethylformamide dimethyl acetal refluxed for 1 h, excess reagent removed under reduced pressure, the residue treated with toluene and methyl iodide for 1 h, solvent removed, fresh toluene added, and refluxed for 2 h 63 mg 3a-formyloxyandrost-5-ene. Elimination takes place with axial alcohols having a suitably disposed trans-hydrogen atom. F.e. and with diterpenoids (aphidicolin, foliol) s. M.J. Ackland et al., J. Chem. Soc. Perkin Trans. 11988, 2013-7. 

Sclareolide 31, a minor constituent of some plant extracts, can be prepared by oxidation of sclareol or manoyl oxide derivatives. The microbial oxidation of sclareolide by M. plumbeus ATCC 4740 was less productive than the oxidation of sclareol, but afforded, beside 3 (3-hydroxy and 3-keto derivatives, a small amount of l 3-hydroxy sclareolide [18]. Similar results and, in addition, the formation of 1,3-dihydroxylated derivatives have been obtained by incubation with Curvularia lunata, in higher conversion yields [35]. Cephal-osporium aphidicola, a fiingus producing the hydroxylated diterpenoid aphidicolin, was shown to hydroxylate sclareohde at the 3 position and, in addition, to afford a 33,6p-dihydroxylated derivative in substantial yields [36]. 

Aphidicolin, a tetracyclic diterpenoid, is a potent inhibitor of mammalian nuclear DNA polymerases, It does not affect mitochondrial DNA polymerase. 

The partial synthesis from epicandicandiol of some C- and H-labelled kaurene derivatives has been described.These have possible application in the study of the biosynthesis of the Isodon diterpenoids. The syntheses of [17- C]kaur-16-en-20-ol from enmein and of 3-oxygenated derivatives of [17- C]kaur-16-ene from ent-3jS,19-dihydroxy-kaur-16-ene have also been described. The synthesis of radioactive aphidicolin has also been reported. It has been shown ° that ent-kaur-15-ene is formed by the dwarf mutant (ds) of maize in place of ent-kaur-16-ene. 

The biological activity of the diterpenoids of the aphidicolin-stemodin series makes these compounds attractive targets. The total synthesis of stemodin (96) has been described.172 The key spiro-centre at C-9 was constructed by the internal aldol condensation of the keto-aldehyde (97) to afford (98). Several stereoselective syntheses of aphidicolin have been reported with different solutions to the problem... 

Aphidicolin is a diterpenoid metabolite of Cephalosporium aphidicola and Phoma betae. The strueture of aphidieolin (5.126) was established in 1972 through a eombination of ehemieal, spectroseopie and X-ray crystallographic studies. Unlike the ent-kaurene and gibberellin metabolites of G. fujikuroi, aphidicolin possesses an absolute stereochemistry that is steroid-like . It has attracted considerable interest as a specific inhibitor of DNA polymerase a and as a potential anti-viral and anti-tumour agent. 

Dalziel W, Hesp B, Stevenson KM, Jarvis JAJ. The structure and absolute configuration of the antibiotic aphidicolin a tetracyclic diterpenoid containing a new ring system. J Chem Soc Perkin Trans I 2841-2451, 1973. 

Generally, terpenoids have been believed to be biosynthesized via acetate-mevalonate pathway. Aphidicolin, a tetracyclic diterpenoid isolated from moulds, Cephalosporium aphidicola [47] and Nigrospora sphaerica [48], was also proved to be biosynthesized from mevanonic acid [49]. In this pathway, isopentenyl pyrophosphate (IPP), geranylgeranyl diphosphate (GGPP), labdane-type and pimarane-type diterpenoids were proposed to be intermediate precursors of aphidicolin [50]. 

Scopadulan-type diterpenoids were supposed to be biosymthesized through similar route to that of aphidicolin. However, a non-mevalonate pathway was considered to be involved in this biosynthetic pathway. 

Aphidicolin (89) is a diterpenoid tetraol produced by the mold Cephalosporium aphidicola. In 1972, Hesp and co-workers reported its isolation and structure [50]. Aphidicolin (89) displays marked activity against Herpes simplex type I virus in cultures of human embryonic cells, as well as antifeedant properties. Furthermore, aphidicolin (89) exhibits antitumor activity in the C6 mouse colon and B16 mouse melanosarcoma screens and has been shown to inhibit the growth of leukemic T- and B-lymphocytes [51]. Such results have stimulated interest in clinical investigations of the effectiveness of 89 against human tumors. 

Aphidicolin is a tetracyclic diterpenoid, produced by the fungus Cephalosporium aphilicola. It has the ability to inhibit HSV-1, -2, VV and herpetic keratitis of rabbit [19]. The mechanism of this compound is not yet established. 

The Mann group demonstrated a new approach to the skeleton of the aphidicolin diterpenoid 54. Treatment of tosylhydrazone 52 with aprotic Bamford-Stevens conditions afforded the required alkene 53. 

In another microorganism, Cephalosporium aphidicola IMI 68689, sequential biosynthetic hydroxylations of the precursor aphidicolan-16p-ol 45, first at C-18, then at C-3, and finally at C-17, give aphidicolin 46, a diterpenoid tumor inhibitor [61,62]. 

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