Camptothecine from Camptotheca acuminata

Camptothecins. The alkaloid camptothecin from Camptotheca acuminata (Nyssaceae) and Mappiafoetida (Icacinaceae) has a pyranoindolizoquinoline structure (Phe pyridine C4N C5N C5L) involving the fusion of quinoline (Phe pyridine), indolizidine (C4N C5N ) and C5 lactone (C5L) rings. Camptothecin is a topoisomerase I inhibitor and is a potent cytotoxic and antitumour compound that is used clinically as an anticancer... 

P. nuda is common in tropical forests from Southern Brazil [142], The MIA strictosamide is the major alkaloid from P. nuda [143], being previously isolated from other plants [144], It is considered an important biosynthetic precursor of the antitumor alkaloid camptothecin, from Camptotheca acuminata [145]. From South American Psychotria species, strictosamide was isolated from P. leiocarpa, P. suterella, P. bahiensis, and/, myriantha [137, 141, 146, 147]. 

Representatives of another important class of plant-derived semisynthetic compounds are the camptothecin (27) derivatives, irinotecan (28) and topotecan (29). Camptothecin (27) was originally discovered as an antileukemic agent in a mouse model when isolated from Camptotheca acuminata Decne. Compounds (28) and (29) are both employed in cancer chemotherapy. These substances are important mechanistically because of their activity against the enzyme, topoisomerase I. These compounds were designed to address efficacy and toxicity concerns with the parent compound, camptothecin, and its sodium salt. ... 

Camptothecin (Figure 6.93) from Camptotheca acuminata (Nyssaceae) is a further example of a quinoline-containing structure that is actually derived by modification of an indole system. The main rearrangement process is that the original (>-carboline 6-5-6 ring system becomes a 6-6-5 pyrroloquinoline by ring expansion of the indole... 

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. 

Camptothecin (CPT, Cl) is a potent antitumor pentacyclic alkaloid isolated from Camptotheca acuminata Decne. (Nyssaceae family) and originating in China (36, 37). Interest in CPT was sparked by the discovery that its primary cellular target is DNA topo I (38). 10-Hydroxycamptothecin (C2), which also occurs naturally, has a better therapeutic index and is used in China for treating many cancers. 

Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Sim GA. Plant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata. J. Am. Chem. Soc. 1966 88 3888-3890. 

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... 

The alkaloid camptothecin (66) from Camptotheca acuminata (Nyssac.) has created much interest recently.When tested against leukaemia L-1210 in mice... 

Camptothecine isolated from Camptotheca acuminata is also an antineoplastic alkaloid, but is very toxic. Chemical modification have decreased its toxicity, and the compound (6) is now in use as a clinical agent [2]. 

Among the alkaloids in this chapter derived from tryptophan, some do not retain the original nucleus of tryptophan, such as quinine, obtained from Cinchona plants (Rubiaceae), camptothecin, originally from Camptotheca acuminata (Cornaceae), and pyrrolnitrin of microbial origin. 

Wall, M. E., M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail, and G. A. Sims, Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, J. Am. Chem. Soc., 88, 3888-3890 (1966). 

Camptothecin (1) was first isolated from Camptotheca acuminata Decne (Nyssaceae) [1, 39] which has been used for many years as a traditional Chinese medicine. Extensive studies of the natural distribution of this unique alkaloid led to its isolation from several plant families Nothapodytes foetida [40-43], Ophiorrhiza mangos [44], Ervatmia heyneana [45], Merrilliodendron... 

Lorence A, Medina-Bolivar F, Nessler CL (2004) Camptothecin and 10- hydroxycamp-tothecin from Camptotheca acuminata hairy roots. Plant Cell Rep 22 437-441... 

Several enzymes can react with sterically hindered compounds. For example, the acetate of a tertiary alcohol can be hydrolyzed by papain in buffer-ethyl acetate (pH 6.5) with excellent -value (>400), affording the ( )-alcohol in 49% yield and 98% ee and the (S)-acetate in 50% yield and 99% ee. The remaining (S)-acetate was converted to 20(S)-camptothecin, which is a pentacyclic alkaloid with potent antitumor activity isolated from Camptotheca acuminata. The product ( )-acetate can be converted to the starting racemic acetate chemically in 70% yield (Fig. 10.22). 

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],... 

Camptothecin is a plant alkaloid obtained from the Camptotheca acuminata tree. It was first evaluated clinically, as a sodium salt, in the 1960s and 1970s, but was abandoned because of severe and unpredictable hemorrhagic cystitis (3,4). Irinotecan (CPT-11) and Rubetecan are semisynthetic, water-soluble derivatives of camptothecin possessing... 

Figure 10.6 The antitumoral camptothecin (CPT), a lipophilic drug extracted from the Chinese tree Camptotheca acuminata, can be incorporated into the liposome bilayer due to its lipophilic character. The CPT-containing liposomes are studied as antitumor drug formulations. (Modified from Stano et al 2004.)...

Camptothecin (1) was first extracted from the hcartwood of the tree species Camptotheca Acuminata Nxssaceac by Wall1 in 1966. Its structure was verified by X-ray analysis2 of its C-20 iodoaceiale ester. 

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. 

Irinotecan (1) is a derivative of the pentacyclic quinoline alkaloid camptothecin (2) the latter was first isolated from the heartwood of the tree species Camptotheca acuminata (Nyssacea) by Wall et al. in 1966.1 Two years later A. T. McPhail and G. A. Sim determined the structure of 2 by X-ray analysis.2... 

Induction of strand breakage may result from inhibition of topoisomerase. The epi-podophyllotoxins etoposide and tenoposide interact with topoisomerase II, which functions to split, transpose, and reseal DNA strands (p.276) these agents cause strand breakage by inhibiting resealing. The te-cans topotecan and irinotecan are derivatives of camptothecin from the fruits of a Chinese tree (Camptotheca acuminata). They inhibit topoisomerase I, which induces breaks in single-strand DNA. 

Camptothecin (1) was first isolated in 1966 from the Chinese tree camptotheca acuminata [1]. As shown in Fig. 1, the five rings of the natural compound are named A, B, C, D and E. The stereo-genic center in the E ring is 5-configured. The antitumor activity of camptothecin quickly made the compound an interesting target for synthetic chemists. After a short time, successful total syntheses were reported. Especially three synthetic approaches should be mentioned here ... 

Camptothecin (CRT, 6, Figure 2.2) was first isolated from the Chinese ornamental tree Camptotheca acuminata Decne, also known as the tree of joy and tree oflove. It occurs in different plant parts such as the roots, twigs, and leaves. It is a member of the quinoline alkaloid group and consists of a pentacyclic ring structure that includes a pyrrole quinoline moiety and one asymmetric center within the a-hydroxy lactone... 

---