Camptothecin drugs derived from

Camptothecin was discovered as an active anticancer drug isolated from the bark of Camptotheca acuminata. The anticancer activity of camptothecin was discovered in the 1960s by the National Cancer Institute (NCI) as part of a systematic effort to screen for novel anticancer agents derived from natural products. Monroe Wall and Mansuhk Wani identified the chemical structure of camptothecin. They also identified the chemical structure of taxol, again under the auspices of the NCI. Susan Hoiwitz was contracted by the NCI to elucidate the anticancer mechanisms of camptothecin. She found in the early 1970s that camptothecin induced DNA breaks and attested DNA and RNA synthesis. However, it is approximately 12 years later, only after DNA topo-isomerase I (Topi) had been identified in human cells, that Leroy Liu and his coworkers found that Topi was the cellular target of camptothecin [reviewed in [1]. 

First generation of topi inhibitors were developed as drugs from camptothecins, a family of compounds derived from wood and bark of the Chinese tree Camptotheca acuminata) [9, 10], Many of these are already in clinical use or clinical trials, including irinotecan, topotecan, exatecan, rubitecan, and lurtotecan. Irinotecan (CPT-11) is bioactivated in liver by carboxylesterase to the active metabolite SN-38, 1000-fold more active [11]. Irinotecan received in 1998 FDA approval for treatment of metastatic colorectal cancer after failure of treatment with 5FU [12],... 

Another area in which natural products have had a major impact on longevity and quality of life is in the chemotherapy of cancer. In fact, most major anticancer drugs are derived from plants or microorganisms (see Chapter 62). Examples include bleomycin, doxorubicin, daunorubicin, vincristine, vinblastine, mitomycin, streptozocin, and most recently, additions of paclitaxel (Taxol ), ironotecan (a camptothecin derivative), and etoposide and tenoposide (podophyllo-toxin derivatives). 

Camptothecin, a plant alkaloid derived from Camptotheca acuminata, is a potent inhibitor of DNA topoisomerase I. Clinical trials failed to show expected antitumor activity, and the drug produced severe, unpredictable toxicity. The camptothecin analogs irinotecan and topotecan were synthesized to reduce toxicity and improve therapeutic... 

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... 

Commercial evidence also supports the case for natural products. Of the 20 best-selling non-protein drugs in 1999, nine were either derived from or developed as the result of leads generated by natural products (e.g., simvastatin, lovastatin, ciprofloxacin, clarithromycin and cyclosprin) with combined annual sales of greater than US 16 billion. Newer developments based on natural products include the antimalarial drug artemisinin, and the anticancer agents taxol, docetaxel and camptothecin. In addition to the historical success in drug discovery, natural products are likely to continue to be sources of new commercially viable... 

Among the worldwide total of 30000 known natural products, about 80% stems from plant resources. The number of known chemical structures of plant secondary metabolites is four times the number of known microbial secondary metabolites. Plant secondary metabolites are widely used as valuable medicines (such as paclitaxel, vinblastine, camptothecin, ginsenosides, and artemisinin), food additives, flavors, spices (such as rose oil, vanillin), pigments (such as Sin red and anthocyanins), cosmetics (such as aloe polysaccharides), and bio-pesticides (such as pyrethrins). Currently, a quarter of all prescribed pharmaceuticals compounds in industrialized countries are directly or indirectly derived from plants, or via semi-synthesis. Furthermore, 11% of the 252 drugs considered as basic and essential by the WHO are exclusively derived from plants. According to their biosynthetic pathways, secondary metabolites are usually classified into three large molecule families phenolics, terpenes, and steroids. Some known plant-derived pharmaceuticals are shown in Table 6.1. 

Camptothecin, an alkaloid isolated from a Chinese tree Camptotheca acuminate), is a potent cytotoxic agent, acting by the inhibition of DNA topoisomerase I. Derivatives that are fluorinated on the aromatic ring A have been studied, leading to two drug candidates for cancer therapies (Figure 8.7) ° exatecan is in Phase IB development,and diflomotecan is an E-homocamptothecin currently in Phase II trials for several solid cancers. 

Cositecan (Karenitecin , BNP 1350) 54 (BioNumerik and ASKA Pharmaceutical) is currently being evaluated in a Phase III trial for the treatment of patients with advanced ovarian cancer who have become resistant to platinum and taxane drugs.110 Cositecan 54,111 114 which is also being evaluated against solid tumours in a Phase I trial, is an orally bioavailable, lipophilic 7-[2-(tri-methylsilyl)ethyl] derivative of camptothecin 55 which is less sensitive to both common and camptothecin-specific resistance mechanisms. Camptothecin 55 was first isolated in 1958 from Camptotheca acuminata (Nyssaceae) and its structure was reported in 1966.115 117 Camptothecin 55 was later shown to be a topoisomerase I inhibitor two camptothecin derivatives, topotecan and iri-notecan, are approved for chemotherapy use. 

A few years after the introduction of Taxol in 1996, further phytogenic anticancer drugs were launched to treat advanced cancers. Topotecan, marketed by Smith Kline Beecham under the trade name of Hycamtin, was approved by the FDA to treat ovarian cancers that have resisted other chemotherapy drugs. Furthermore, irinotecan was introduced by Pharmacia Upjohn under the trade name of Camptosar for the treatment of metastatic cancer of the colon or rectum. Both compounds are derivatives of camptothecin which was isolated from the Chinese tree Camptotheca acuminata, well known in Chinese Traditional Medicine for anticancer treatment [65]. Isolation of the bioactive principle camptothecin and its structure elucidation had already been performed in 1966... 

Analogs based on a novel template, ll-aza-(20S)-camptothecin 219, were obtained from a total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay. The parent ll-aza-(20S)-camptothecin 219 is derived by cyclization of the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidine 217 and optically active tricyclic ketone 218 in 27% yield (Scheme 47) (95JMEn06). 

Quinine (80) is a common quinoline derivative and an important antimalarial isolated from Cinchona bark (see Chapter 1 and compound number 1 in Section 1.1). Another antimalarial compound is Primaquine (81). Camptothecin (82) is an important anticancer drug that contains the quinoline unit. In all cases, the quinoline unit is highlighted in blue in the illustration. A typical isoquinoline derivative is papaverine (83), which is related to morphine and also isolated from the opium poppy. Papaverine relaxes smooth muscle tissue in blood vessels. Once again, the isoquinoline unit is highlighted. 

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