Camptothecins

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). 

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

Nothapodytes foetida (Icacinaceae) (55, 56). From Ophiorrhiza mungos (Rubi-aceae), camptothecin and 10-methoxycamptothecin have been obtained, and from Ervatamia heyneana (Apocynaceae), camptothecin and 9-methoxycamptothecin (59). From Merrilliodendron megacarpum (Icacinaceae), camptothecin and 9-methoxycamptothecin have been isolated (3). Table 5.2.5 lists yields from various plants. 

The content of camptothecin in different parts of C. acuminata has been investigated, when it was found that the content in the fruit or root bark is higher than that in the stem bark (22, 97). The content of camptothecin in N. foetida was higher than that of any other plants. 

Genus/species Plant part Camptothecin (%) 9-Methoxy camptothecin (%) 

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Synthesis of camptothecin (163) is another example[133]. The iboga alkaloid analog 164 has been synthesized smoothly by the intramolecular coupling of iodoindole and unsaturated ester to form an eight-membered ring. Af-Methyl protection of the indole is important for a smooth reaction[134]. An efficient construction of the multifunctionalized skeleton 165 of congeners of FR900482 has been achieved[135]. 

The pentacyclic plant alkaloid camptothecin has been a popular synthetic target because of its antitumor activity. Retrosynthetic disconnection to tricyclic intermediate A and chiral lactone B followed from multistrategic planning. 

The total syntheses of fredericamycin 71 and camptothecin 72 made use of similar strategies. N-Sulfonyl-l-aza-1,3-butadienes in conjunction with electron rich dienophiles participated in the inverse electron demand Diels-Alder reaction to afford pyridines after treatment with base. 

In a six-step synthesis of (5)-camptothecin (20010L4255), the final step involved a C-ring closure using the Heck reaction. As shown in Scheme 17, 2-chloroquinoline 146 was treated with 15% (PPh3)2Pd(OAc)2 and two equivalents KOAc in CH3CN at 100 °C, affording (5)-campotothecin (147) in 64% yield. 

Scheme 14. Glaxo s formal asymmetric synthesis of camptothecin (55).

Camptothecins (irinotecan, topotecan) are derived from the bark of the Chinese tree Xi Shu (Camptotheca accuminata). They inhibit topoisomerase I thus effecting double strand breaks. Unwanted effects include diarrhea and reversible bone marrow depression. 

Camptothecin is a plant alkaloid that selectively targets topoisomerase I (Topi). It produces DNA damage leading to the destruction of eukaryotic cells. Because... 

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]. 

Camptothecin is highly insoluble, which facilitated its crystallization and chemical structure determination. 

The first clinical trials were performed in the 1970 s using a sodium salt derivative with an open E-ting (Fig. 1). However, the clinical efficacy was limited and severe bladder toxicity led to the termination of the clinical trials. The poor efficacy of the camptothecin sodium salt in those clinical trials was probably due to the fact that the open E-ring form of camptothecin (carboxylate derivative) is inactive as a Topi inhibitor. Following the identification of Topi as a target of camptothecin, water-soluble derivatives were produced by the pharmaceutical industry. Two of these water-soluble derivatives have been approved by the FDA for cancer treatment in the early 2000s topotecan and irinotecan. 

Cancer cells are killed by camptothecins as a result of the trapping of Topi-DNA cleavage complexes. Those... 

Camptothecins. Figure 3 Conversion of reversible Topi -DNA cleavage complexes into DNA damage by collision of a replication fork (the DNA polymerase complex is not shown). 

The parent, unsubstituted isochromanone has been caused to react with a variety of aromatic amines to prepare Ar-substituted 1,4-dihydro-3(2.ff)-isoquinolones,4 and with amines to give amides.5 The 6,7-methylenedioxy-3-isochromanone was an intermediate in the synthesis of protopine and its allied alkaloids,6 and for the synthesis of the berberine ring system.7 The 6-methoxy analog was prepared as a potential intermediate in a camptothecin synthesis8 and 8-methoxy-4,5,6,7-tetramethyl-3-isochromanonc was an intermediate in the synthesis of sclerin.9 The compound herein described was the basis of a facile synthesis of ( l )-xylopmins,10 and its reaction with hydrazine has been reported.11... 

The procedure may have considerable scope, as shown by the synthesis of a heterocyclic lactone which is an important intermediate in the synthesis of eZ,Z-desoxycamptokhecin, which on oxidation gave camptothecin.12... 

Bicyclic 2-pyridones fused over the nitrogen is another important heterocyclic scaffold. In the quest towards the total synthesis of Camptothecin, Danishefsky and co-workers developed a method where a vinylogous urethane was reacted with 1,3-dicarboxymethoxyallene generated in situ from dimethyl 3-chloroglutaconate to a bicyclic 2-pyridone intermediate [31-34]. This method has later been successfully applied in the synthesis of other... 

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]. 

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