Camptothecin derivatives, anticancer

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). 

As in the case of microbially derived anticancer agents (Section IV.E.2.), interested readers can consult the information on podophyUotoxin and derivatives, the vinca alkaloids and derivatives, and camptothecin and derivatives in the recent volume edited by the authors of this chapter. 

In 1985, It was reported by Hsiang et al. [30] that the cytotoxic activity of camptothecin (CPT) was attributed to a novel mechanism of action involving the nuclear enzyme topoisomerase I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. From the cytotoxic data [31] of camptothecin derivatives (VI) against SKOV-3 human ovarian cancer cells, Eq. 7 was derived [21] ... 

Early and delayed onset diarrhoea is often induced by CPT-11 [25,156,157], and can be a dose-limiting factor for this drug. Delayed onset diarrhoea is not a rare adverse effect when using anticancer agents, but the early onset observed during or immediately after injection is almost specific to CPT-11. It is important to clarify the mechanism(s) of this toxicity in order to obtain a less toxic camptothecin derivative. 

Plant-derived alkaloids are widely used in many purposes that include analgesics (morphine and codeine), stimulants (caffeine and nicotine), anticancer agents (vincristine, vinblastine, and camptothecin derivatives), gout suppressant (colchicine), muscle relaxant (C-tubocurarine, antiarrhythmic ajmaline), antibiotic (sanguinarine), and sedative (scopolamine) [1]. So, different biotechnological approaches are undertaken for the large-scale production of these compounds. 

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]. 

The protected E-ring moiety of (S)-camptothecin has been prepared in enantio-merically enriched form by the enzymatic resolution of a triester with PLE in a pH 7 phosphate buffer-acetonitrile (5 1) solution (Figure 6.7). The alkaloid camptothecin is an inhibitor of the enzyme topoisomerase and some of its derivatives are anticancer drugs [52]. 

Camptothecin (Fig. 4), a quinoline alkaloid, is a potent anti-neoplastic agent that inhibits DNA topoisomerase I. Accumulation of up to 8 mg of camptothecin/L was reported for hairy root cultures of Ophiorriza pumila transformed with A. rhizogenes. Cotyledon-derived calluses of Nothapodytes foetida were able to produce not only camptothecin, but also its derivatives also known to exhibit anticancer activity. 

Another important anticancer natural product is camptothecin, an alkaloid derived from the Chinese tree Camptotheca acuminata Descne. A semisynthetic water-soluble derivative of camptothecin known as ironotecan (Topotecin , Campto ) was introduced in Japan in 1994 for the treatment of lung, ovarian, and cervical cancers. Unlike Taxol, camptothecin acts by inhibition of the enzyme topoisomerase I. 

During the course of clinical development, it is often important to identify the structures of metabolites. This information provides an opportunity to better understand interpatient variability in pharmacokinetics and toxicity. Clinical studies performed by Lokiec and coworkers, 1996 on a semisynthetic derivative of 20(S)-camptothecin, CPT-11, demonstrate the use of LC/MS to investigate the in vivo metabolic pathways. CPT-11 is a potent inhibitor of topoisomerase II, which is an enzyme involved in DNA duplication, and exhibits significant activity against various types of tumors in clinical studies. The understanding and control of the main biotransformation pathways are particularly important for anticancer drugs because therapeutic doses are often close to the maximum tolerated dose. 

A variety of plant substances with planar, polycyclic, aromatic structures can intercalate with DNA, examples being the quinoline alkaloid camptothecin and the furanocoumarin phenolic psoralen (Table 12.1). A variety of plant-derived anthraquinones and naphthoquinones bind to DNA and it is notable that the structurally related anthraquinones mitox-antrone and adriamycin are clinically employed as anticancer drugs (Table 12.1). DNA-binding compounds that interfere with DNA repair, DNA replication and gene expression are cytotoxic and have potential as anticancer agents (see Chapter 9). 

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... 

The camptothecins are a new class of very promising anticancer agents, several derivatives of which are in clinical use.83 Prodrug 53 (Figure 11.8) of 9-aminocamptothecin showed 20- to 80-fold reduced toxicity in comparison with 9-aminocamptothecin.84 The prodrug was readily cleaved by p-glucuronidase in vitro. 

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