Camptothecins antitumor natural products

The discovery of Taxol is a fruit of a National Cancer Institute (NCI)-sponsored project on identification of antitumor agents from natural resources. Bioassay-guided fractionation led to the isolation of this unique compound from Taxus bre-vifolia (pacific yew). Wani et al. also identified another famous antitumor natural product camptothecin. Unlike camptothecin, which was abandoned in the phase of clinical trial because of its severe toxicity, Taxol was almost discarded at the preliminary phase because it only exhibited moderate in vitro activity toward P388, a murine leukemia cell line that was used in the standard evaluation system by NCI researchers at that time. However, it was rescued by a subsequent finding of its strong and selective antitumor activities toward several solid tumors, and more... 

The aza-annulation methods developed for conversion of 88 to 94 were extended to the synthesis of the antileukemic and antitumor natural product ( )-camptothecin (125, Scheme 11 ).47 Aza-annulation of 109 with 121 in the presence of NaBH4 resulted in heterocycle formation to give 122 without subsequent elimination of the malonate species. A dye sensitized photo-oxidation promoted the rearrangement of the indolo[a]quinolizinone ring to the indolizino[l,2-h]quinolone ring 123. Compound 123 was converted to 124, which constituted a formal total synthesis of camptothecin (125). 

The tetracyclic A/B/C/D ring core of (205)-camptothecin, one of the most potent antitumor natural products isolated from Camptotheca acuminate, was prepared by a combined directed ortho metallation/cross-coupling strategy. Snieckus showed that 2-bromo-6-methoxypyridine (152) could be sequentially treated with ter/-butyllithium (2 equiv) at -78 °C and anhydrous zinc bromide. The resulting organozinc species was then subjected to palladium-catalyzed cross-coupling reaction with triflate 153 to afford the biaryl 154, a precursor to the tetracyclic A/B/C/D ring core 155. 

The antitumor activity displayed by camptothecin (28) and its analogues has led to a great deal of interest in such compounds.36 Camptothecin is a complicated alkaloid to isolate, and analogues, which are of biological interest, are synthesized from the natural product itself.37 This need to access a wide range of analogues has led to a need for synthetic studies directed toward the development of a concise, yet inexpensive, total synthesis of camptothecin. 

Finally, it may be worthwhile to point out that one of the most successful chemotherapeutic drugs provided by nature may be considered as a non-classical active-site-directed irreversible inhibitor This drug is penicillin (70). As a non-classical antimetabolite of D-alanyl-D-alanine, it first forms a reversible complex with the enzyme peptidoglycan transpeptidase, and then by a ringopening reaction of its p-lactam moiety, it forms a covalently linked penicil-loyl-enzyme complex97. However, the reaction involves the acylation of a sulfhydryl group in the active site of the enzyme in this respect, 70 resembles the classical-type endoalkylating antimetabolites, azaserine and DON (8 and 9, see Section 2.2.). Some of the more recently discovered antibiotics and natural products from plants with antitumor activity (e.g., camptothecin) are... 

Although not listed in the tables, at least four other natural product drugs have given yeoman service in the antitumor area. The first of these is paclitaxel (Taxol ) which sold US 1.6 billion in 2000 this is followed by the vinca alkaloids vinblastine and vincristine. Completing the quartet are the natural product-derived epi-podophyllotoxin derivatives teniposide and etoposide and the materials derived from camptothecin, topotecan and CPT-11. These will probably not be the only natural product drugs in the antitumor field, as can be seen by inspection of Table 6.3, where Cragg and Newman recently reported on the source... 

In the area of nitrogen-containing natural products the following have been glycosylated the antitumor alkaloid 20(S)-camptothecin, the ergot alkaloids elymoclavine, chancoclavine, lysergol (en mic reaction), and castanospermine. ... 

---