Camptothecin and its analogues

As part of the scope of this review, the extensive studies by Curran towards the synthesis of camptothecin and its analogues by radical... 

Camptothecin and its analogues, 34 (1997) 69 Cancer, aromatase inhibition and breast, 26... 

Camptothecin and its analogues (22) have been also found in other plants. 9-Methoxycamptothecin, camptothecin, and mappicine have been isolated from... 

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... 

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. 

Curran and coworkers [141] developed a palladium(0)-catalysed domino process for the synthesis of the very potent anticancer natural product (S)-camptothecin (283) [142] and its analogues (Scheme 8.70). Camptothecin (283) contains an ll//-indolizino[l,2- ]quinolin-9-one skeleton, which is also found in mappicine [143] and the promising new analogue DB-67 (287) [144]. A domino-radical reaction has been used for its construction in 40-60% yield [145]. However, the product is also accessible from the isonitrile 284... 

These cyclohexano pyranosides, cyclopentano furanosides, and their transformation products promise to be valuable synthons judging from recent efforts directed towards biomimetic synthesis of camptothecin (196) and its analogues from the congener (195) by Hutchinson and co-workers 61). 

Figure 5.17 shows the interconversion of the lactone form of a semisynthetic analogue of camptothecin to its ring-opened carboxylate form. The lactone form predominates in low pH whereas the ring-opened carboxylate form prevails at neutral and alkaline pH, as illustrated in Figure 5.18. 

The basic structure of camptothecin. Analogues of camptothecin that are used to treat various neoplastic diseases involve substitutions at positions C-7, C-9, and C-11 of the basic molecule. All analogues as well as the parent molecule bind to topoisomerase 1 and interfere with its functions during DNA replication. 

The closely related camptothecin 133 is more complicated because it is chiral. Close analogues (topotecan and irinotecan) are in use as anti-cancer drugs. As these compounds differ only by substitution on the quinoline, synthesis of the enantiomerically pure pyridone 135 is obviously of prime importance. 

Camptotheca acuminata (Nyssaceae) is a tree that grows throughout the southern part of China. From its stem wood, camptothecin has been obtained (160). Camp-tothecin is notable because of its remarkable antitumor and antileukemia activity. The other minor camptothecin analogues that have been obtained are 10-methoxy-camptothecin (161), and 20-deoxycamptothecin (1). 11-Hydroxycamptothecin and 11-methoxycamptothecin have been obtained from the fruit (68, 98). 

---