I Camptothecin

A recently reported total synthesis of carboxylic acid (169).228 To accomplish the... 

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]. 

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... 

In an effort to improve the water solubility of camptothecin, Rahier et al. [50] synthesized four 20-O-phosphate derivatives (VI). These compounds are freely water-soluble, stable to physiological pH, and stabilize the human topo I-DNA covalent binary complex with the same sequence-selectivity as camptothecin itself All four compounds inhibited the growth... 

Vladu et al. [51] synthesized a series of 7-X-lO-Y-camptothecins (VII) and evaluated their ability to trap hiunan DNA topo I in cleavable complexes. We used these data to develop Eq. 5 (Table 3) ... 

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

A series of indeno[l,2-c]isoquinolines have been described [27] and INO-lOOl has been investigated in the clinic. Although the structure of INO-lOOl has not been reported, sulfonamide 28 is a representative structure (IC50 = lnM, EC5O = 10nM). CEP-9722 is in Phase I clinical trials, while its exact structure has not been disclosed, it is a prodrug of CEP-8983 (29) and patent applications highlight 30. Preclinical efficacy in combination with TMZ and camptothecin have been... 

The major class of topoisomerase I inhibitors comprise of the camptothecins, while topoisomerase II inhibitors fall into several classes - anthracyclines (e.g. doxorubicin), anthracenediones (mitoxantrone), anthrapyrazoles (bianthrazole), actinomycins (actinomycin D), acridines (m-AMSA), ellipticines (9-hydroxy-ellipticine) and epidophyllotoxins (Etoposide (VP-16) and VM-26). The chemical... 

UGTIAI has an important role in the metabolism of irinotecan, etoposide, epiru-bicine, and tipifamib. Irinotecan is a camptothecin derivative used in the treatment of metastatic colon cancer. Irinotecan is a prodrug since it is activated to Ethyl-10-hydroxycamptothecin (SN-38) by carboxyl esterase to exert its antitumor activity mediated by the inhibition of topoisomerase I. SN-38 undergoes UGTIAI-catalyzed glucuronide conjugation to form the inactive SN-38 glucuronide (SN-38G). 

Camptothecin (84) Quinoline alkaloid Karenitecin Oncology Inhibits topoisomerase I Phase III BioNumerik and 149,... 

Lavergne O, Harnett J, Holland A, Lanco C, Lesueur-Ginot L, Demarquay D, Huchet M, Coulomb H, Bigg DC. (1999) BN 80927 A novel homo-camptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett 9 2599-2602. 

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. 

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. ... 

Muggia FM, Creaven PJ, Hansen HH, Cohen MH, Selawry OS. Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880) correlation with preclinical studies. Cancer Chemother Rep 1972 56(4) 515-521. 

Kohn KW, Pommier Y. Molecular and biological determinants of the cytotoxic actions of camptothecins. Perspective for the development of new topoisomerase I inhibitors. Ann NY Acad Sci 2000 922 11-26. 

Hsiang YH, Hertzberg R, Hecht S, Liu LF. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 1985 260(27) 14873-14878. 

Hennequin C, Giocanti N, Balosso J, Favaudon V. Interaction of ionizing radiation with the topoisomerase I poison camptothecin in growing V-79 and HeLa cells. Cancer Res 1994 54(7) 1720-1728. 

Chen AY, Okunieff P, Pommier Y, et al. Mammalian DNA topoisomerase I mediates the enhancement of radiation cytotoxicity by camptothecin derivatives. Cancer Res 1997 57 1529-1536. 

Camptothecin, an inhibitor of topoisomerase i. Is an effective anticancer agent that converts the enzyme to become a DNA-damagIng agent. 

The topoisomerase I inhibitors include irinotecan and topotecan. They are water-soluble camptothecin analogues. Both are administered by intravenous infusion. Their cytotoxicity effects are exerted through interaction with the topoisomerase I-DNA complex, eventually leading to cell death. 

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