Camptothecin enzyme inhibition

An ethyl group at position 20 also appears to be specifically recognized by the enzyme-DNA complex, because no modifications of this group have increased activity. It should be noted that compound (37), in which the exocy-clic methylene group was expected to provide a more electrophilic alkylation target, exhibited potent camptothecin-like inhibition of Topo I activity [93]. 

On the other hand, salivation and abdominal pain [24, 157,165] were reported in early clinical studies and these symptoms possibly arise from a cholinergic mechanism. Therefore, CPT-11 probably possesses acetylcholine-like activity. In fact, it was shown that CPT-11 and some of camptothecin derivatives inhibit acetylcholinesterase activity with IC50 (concentration inducing 50% inhibition) values of 1.6 //M or less [107]. Inhibition of this enzyme causes an increase in acetylcholine level and induces cholinergic action. After a 90 min intravenous infusion of CPT-11 at 50-150 mg/m in hu-... 

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

Note THF = tetrahydrofuran BHT = butylated hydroxytoluene, an antioxidant Camptothecin (CM) = causes inhibition of the DNA enzyme topoisomerase (Top 1) which induces DNA damage and apoptosis DHT = dihydrotestosterone PrEC = normal prostate stromal cells LNCaP, PC-3, DU-145 = neoplastic prostate epithelial cells (See Table 21.1). 

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. 

The camptothecins are natural products that are derived from the Camptotheca acuminata tree, and they inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of the enzyme results in DNA damage. Topotecan is indicated in the treatment of patients with advanced ovarian cancer who have failed platinum-based chemotherapy and is also approved as second-line therapy of small cell lung cancer. The main route of elimination is renal excretion, and for this reason caution must be exercised in patients with abnormal renal function, with dosage reduction being required. 

Figure 7.11 Examples of topoisomerase inhibitors. Ellipticene acts by both intercalation and inhibition of topoisomerase II enzymes. It is active against nasopharyngeal carcinomas. Amsacrine is used to treat ovarian carcinomas, lymphomas and myelogenous leukaemias. Camptothecin is an antitumour agent...

COMPARE analysis can also be used to identify de novo new classes of compounds directed against known targets. For many yearS/ the camptothecin class of compounds was the only explored class of inhibitors of topoisomerase 1, an enzyme responsible for DNA single-strand breaks and religation. COMPARE analysis/ however/ showed a high correlation between camptothecins and a previously unexplored class of compounds known as indenoisoquinolin.es. Confirmatory testing revealed that the hide no isoquinolines did in fact inhibit topoisomerase I (22). 

Irinotecan (Camptosar), a more selective synthetic analogue of camptothecin (a natural, but toxic, anticancer alkaloid), acts by inhibiting topoisomerase 1, an enzyme involved in ordering the strands of DNA. Some compounds act by physical binding with vital natural polymers - the complex indole alkaloid vincristine is a classic example - it binds to tubulin, a protein essential to cell division. 

Fortunately, studies on camptothecin continued in some laboratories and it was discovered that it had a previously unknown mechanism of action, namely the ability to inhibit topoisomerase I (topo I). The topoisomerases I and II are enzymes that allow chromosomal DNA to undergo changes in topology (i.e., relaxation) prior to replication. Camptothecin was found to inhibit topo I but not topo II, and to do so... 

In 2006, Delfoume et al. repotted the syntheses of two aza-analogs of wakayin and tsitsikammamines A and B based on a 1,3-dipolar cycloaddition reaction between the indole-4,7-dione 48 and a diazo-aminopropane derivative 49 (Scheme 15). One of the two analogs partially inhibits human topoisomerase I, whereas the synthetic intermediates inhibit the enzyme DNA cleavage activity at a concentration comparable to that of the control drug camptothecin [69, 70]. 

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