Colchicine, biosynthesis

For obvious reasons, inhibitors of cholesterol biosynthesis have aroused intense interest. Studies on a variety of species (mostly rats) have been made using 1-alkylimidazoles," colchicine," and chenodeoxycholic acid, the last work being particularly interesting as the metabolite affected HMG-CoA reductase but not cholesterol 7a-hydroxylase, the steps believed to be rate-limiting for the biosynthesis of sterols and of bile acids respectively. Arsenite, /8-mercaptoethanol, dithiothreitol, and ethanethiol all inhibited the biosynthesis of cholesterol from MVA in rat liver homogenates. The accumulation of 4,4-dimethyl-5a-cholest-8-en-3/3-ol together with the corresponding A -diene supported the view that... 

The biosynthesis and isolation of colchicine from C. awtumrude grown in a C 02 atmosphere (295) has provided a source of radioactive material for biological studies. Partial syntheses of radioactive colchicine labeled specifically in the A, B, or C ring have been reported (383). 

Definitive evidence arising from and H-labelling studies points to the intermediacy of (5)-autumnaline (124) in the biosynthesis of colchicine (125). The incorporation of (i S)-[l- C]autumnaline [as (124)] into colchicine (125), with enhancement of the n.m.r. signal for C-7 only, affirms this conclusion. 

Convincing support for the biosynthesis of camptothecin (155) proceeding via the (3S)-lactam (154) comes from feeding experiments with the two lactams [as (154)] labelled with at C-5. Only the (3S)-isomer was incorporated into (155), with enrichment of C-5 only, which is consistent with the pathway illustrated in Scheme 17. The use of C-labelled material in this study is notable as generally the low levels of incorporation found in plants preclude the use of precursors labelled in this way. However, C-labelled precursors can find use where satisfactory incorporations can be obtained and the labelled material is not diluted substantially by unlabelled material, as here and in the case of colchicine biosynthesis (see above). No doubt further applications in the study of alkaloid biosynthesis will appear in the future. 

Amaryllidaceae Alkaloids.—O-Methylnorbelladine (162) and vittatine (163) are implicated as intermediates in the biosynthesis of narciclasine (164). " Loss of the two-carbon bridge from the latter could plausibly occur by a retro-Prins reaction on 11-hydroxyvittatine (165) to give (166), as shown in Scheme 18, analogy for hydroxylation of (163) coming from the biosynthesis of the related alkaloid haeman-thamine.Strong support for this pathway to narciclasine (164) was obtained when it was shown that tritiated (165) was an efficient precursor for this alkaloid.It is to be noted that collapse of a similar j8-hydroxy-amine is proposed for the biosynthesis of colchicine. 

Nasreen, A., M. Rueffer, and M.H. Zenk (1996). Cytochrome P-450-dependent formation of isoan-drocymbine from autumnaline in colchicine biosynthesis. Tetrahedron Lett. 37, 8161-8164. 

The solution to the enigma of the biosynthesis of colchicine (5) is of longer standing. More details on the unexpected but simple pathway to this non-basic alkaloid have come with the publication of full papers. ... 

The unusual structural features of the colchicine molecule have generated a great deal of interest in its mode of biosynthesis. A number... 

The actual pathway used in the biosynthesis of colchicine was initially clarified by the tracer experiments of Leete (6, 58-60), Battersby (61-64), and co-workers. Both C. autumnale and G. byzantium were used in these studies, and similar trends in incorporation of various potential precursors were obtained by both groups. The incorporation data are shown in Table VI and the degradation schemes used to identify individual carbon atoms or groups of atoms are summarized in Fig. 1. 

An important clue to the actual biosynthetic pathway was the discovery that androcymbine (CXVII R = H) occurs along with colchicine-type compounds in A. melanthioides 2, 47). The similarity of CXVII to CXVI was striking, as was the fact that CXVII (R = H) has the same absolute stereochemistry as colchicine [47, 68). This suggested that a 1-phenethylisoquinoline structure might be involved in the biosynthesis of colchicine. This hypothesis, as well as a detailed pathway to colchicine (see Fig. 2), has been brilliantly demonstrated by Battersby and coworkers 68, 69) in recent tracer experiments. 

The incorporation C. autumnale) of 0-methylandrocymbine (CXVII R = CH3, tritium label in the OCH3 at carbon 2) and CXVIII (i C at carbon 6) into colchicine (15 and 10% incorporation, respectively) with no randomization of label indicated the general correctness of the proposed scheme. Multiple labeling experiments with synthetic CXVIII have confirmed many details of the biosynthesis. CXIX was incorporated into colchicine with no change in the ratio, proving that... 

Fig. 2. Battersby, A. R.. et al. Reproduced from Alkaloid biosynthesis. Part XVIII. Biosynthesis of colchicine from the 1-Phenethylisoquinoline system. J. C. S. Perkin Trans. I, 1741 (1972), by kind permission of the Editor...

Pharmacology V., together with vincristine and the semisynthetic vindesine (deacetyl-V.-23-amide), is now established in modem cytostatic therapy (i.v.). It acts in the same was as colchicine (see phenethyltetra-hydroisoquinoline alkaloids) as an inhibitor of mitosis and arrests the metaphase by binding to microtubular proteins. In addition, V. inhibits DNA polymerase and thus also DNA biosynthesis. In combination with other cytostatic agents it is used in therapy for (non)-Hodgkin s lymphomas, testicular, breast, and lung cancer. ... 

---