Cancer cytotoxic activity

Haliclonacyclamine F (25), arenosclerin D (26), and arenosclerin E (27) have been recently isolated from the sponge Pachychalina alcaloidifera endemic in Brazil [26]. The alkaloids 25-27 were isolated from the cytotoxic, antibiotic, and antituberculosis MeOH crude extract of P. alcaloidifera by a series of separations on silica-gel and cyanopropyl-bonded silica-gel columns. The structures of compounds 25-27 were established by the same approach employed for the structural elucidation of haliclonacyclamine E (13) and arenosclerins A-C (14-16) [18], as well as by comparison with NMR data for this last series of alkaloids. The alkaloids 25-27 displayed moderate cytotoxic activity against SF295 (human CNS), MDA-MB435 (human breast), HCT8 (colon), and HL60 (leukemia) cancer cell lines. 

Guerrero, I. C. Andres, L. S. Leon, L. G. Machin, R. P. Padron, J. M. Luis, J. G. Delgadillo, J. Abietane diterpenoids from Salvia pachyphylla and S. clevelandii with cytotoxic activity against human cancer cell lines. J. Nat. Prod. 2006, 69, 1803-1805. 

BS, Bacillus subtilis CA, Candida albicans SA, Staphylococcus aureus SC, Saccharomyces cerevisiae TM, Trichophyton mentagrophytes PN, Penicillium nonatum KB, LOVO (colon cancer), P388 are cell lines in cytotoxic activity testings. 

A major point that needs to be addressed in future work is the targeted delivery of organometallic anticancer drugs to cancer cells only. Also, additional features that generate cytotoxic activity other than disruption of DNA replication, such as the inclusion of molecular fragments that can interfere in cancer cell-specific cellular pathways, could be explored (11,103). 

Initial experiments showed that [0s(ri6-bip)Cl(en)]+ (26) was not cytotoxic towards cancer cells (105), but a later reassessment of the cytotoxic activity of this compound showed that it indeed was active at micromolar concentrations (IC50 values of 7.6 (A2780) and 10 pM (A549)) (112). A possible explanation for the initial lack of activity may be the partial decomposition of the complex in stock test solutions prepared in DMSO, as was evidenced in subsequent studies (112). The cytotoxicity data are now more in line with the chemical properties of the complex, i.e. observed hydrolysis rate and guanine binding. 

A. Bielawska, K. Bielawski, K. Chrzanowski, S. Wolczynski, Prolinase-Activated Prodrug for Cancer Chemotherapy. Cytotoxic Activity of Proline Analogue of Chlorambucil in Breast Cancer MCF-7 Cells , Farmaco 2000, 55, 736-741. 

The dimeric carbazole alkaloids often occur along with the corresponding monomeric carbazoles in terrestrial plants [7,62] (Scheme 7). Clausenamine-A was obtained by Wu from the stem bark of Clausena excavata [63]. Clausen-amine-A and its synthetic analogs, like bis(O-demethylmurrayafoline-A), show cytotoxic activities against diverse human cancer cell lines [64] and exhibit moderate antimalarial activity [65,66]. Furukawa isolated l,r-bis(2-hy-droxy-3-methylcarbazole) and bismurrayaquinone-A, the first dimeric car-bazolequinone alkaloid found in nature, from Murraya koenigii [67]. 

Hassan S, et al. Cytotoxic activity of a new paclitaxel formulation, Pacliex, in vitro and in vivo. Cancer Chemother Pharmacol 2005 55 47. 

Watanabe J, Natsume T, Kobayashi M. (2007) Comparison of the antivas-cular and cytotoxic activities of TZT-1027 (Soblidotin) with those of other anticancer agents. Anti-Cancer Drugs 18 905-911. 

The cytotoxic potential of several resin glycosides has been evaluated against mammalian cancer cultured cell lines. For tricolorin A (106), the most potent cytotoxic activity (ED q 2.2 pg/cm ) was observed with human breast cancer and... 

Recently, Turner et al. described the synthesis of the alkaloid (R)-(-t-)-crispine A, which shows cytotoxic activity against HeLa human cancer cell lines, using in the final step a deracemization procedure with the combination of an enantioselective amine oxidase obtained by directed evolution methods and a chemical non-selective reducing agent (Scheme 10.20) [48]. 

In 1984, Giibble et al. reported for the first time a novel l,10-bis-(6-methyl-5H-benzo[fc]carbazol-ll-yl)decane (469) which has potential bifunctional nucleic acid intercalating properties (406). To function as anti-tumor active drugs, one of the most important cytostatic mechanisms of action of coplanar annelated polycyclic compounds is their intercalation with DNA (405). Ten years later, Kucklander et al. studied a series of 5H-benzo[ 7]carbazole quinone derivatives for their cytotoxic activity against colon and lung cancer cells, and found that the heteroannelated 5H-benzo[ 7]carbazole quinone derivative 470 was the most active among the various analogs (407) (Scheme 4.2). 

In phase II studies with topotecan alone, there is cytotoxic activity in lung cancer with intermittent dose schedules (33), as well as in lung cancer patients with topoisomerase II refractory disease (34). In advanced head and neck cancer topotecan is well-tolerated and has single-agent activity similar to that of cisplatin, 5-fluorouracil, and methotrexate... 

Since the formation of the ethyleniminium ion is crucial for the cytotoxic activity of the nitrogen mustards, it is not surprising that stable ethylenimine derivatives have antitumor activity. Thiophospho-ramide or thiotepa is the best known compound of this type that has been used clinically. Both thiotepa and its primary metabolite, triethylenephos-phoramide (TEPA), to which it is rapidly converted by hepatic mixed-function oxygenases form crosslinks with DNA. It is mainly used as an intravesicu-lar agent in bladder cancer. Thiotepa produces little toxicity other than myelosuppression. 

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