Paclitaxel camptothecin

Paclitaxel, camptothecin, vincristine, vinblastine, and other compounds currently under development as potential anticancer drugs (i.e., the bryostatins isolated from marine dinoflagellates) were discovered through a broad-based screening program to identify, using a whole-cell inhibition assay, natural products that are active against a battery of representative cancer cell lines. 

Ohtsu, H. Nakanishi, Y Bastow, K. R Lee, R.-Y Lee, K.-H. Antitumor agents 216. Synthesis and evaluation of paclitaxel-camptothecin conjugates as novel c3dotoxic agents. Bioorg. Med. Chem., 2003, 11 1851-1857. 

HPMA conjugates of other anticancer drugs such as paclitaxel, camptothecin, and platinates were synthesized and evaluated in both animals and humans. Controlled drug release at the tumor sites was a major challenge for these systems. 

A major advantage of the natural products approach to drug discovery is that it is capable of providing complex molecules that would not be accessible by other routes. Compounds such as paclitaxel (Taxol, 8) or rapamycin (10) would never be prepared by standard "medicinal chemistry" approaches to drug discovery, even including the newer methods of combinatorial chemistry. Likewise, the new approach of combinatorial biosynthesis, although an important one, is unlikely in the near future to yield new compounds of the complexity of paclitaxel and camptothecin. 

Another area in which natural products have had a major impact on longevity and quality of life is in the chemotherapy of cancer. In fact, most major anticancer drugs are derived from plants or microorganisms (see Chapter 62). Examples include bleomycin, doxorubicin, daunorubicin, vincristine, vinblastine, mitomycin, streptozocin, and most recently, additions of paclitaxel (Taxol ), ironotecan (a camptothecin derivative), and etoposide and tenoposide (podophyllo-toxin derivatives). 

Many anticancer agents have their origins in pharmacognosy, including paclitaxel, etoposide, and the camptothecin analogues, topotecan and irinotecan, to name just a few. The dolastatins are a unique class of compounds isolated from the Indian Ocean sea-hare Dolabdla auricularia that are referred to as depsipeptides,... 

In many ways, the development of paclitaxel mirrored that of the camptothecin analogs, both being dogged for many years by supply issues, poor pharmacokinetics, and toxicity, but the subsequent uncovering of novel mechanisms of action fueled renewed efforts to develop these leads into important new anticancer agents (75). 

Preparations of liposomes via SCF processing are designated as critical fluid liposomes (CFLs). CFLs have successfully encapsulated hydrophobic drugs such as taxoids, camptothecins, doxorubicin, vincristine, and cisplatin. In addition, stable paclitaxel liposomes with a size of 150-250 nm were obtained. Aphios Co. s patent (US Patent 5,776,486) on Super-Fluids CFL describes a method that is useful for the nanoencapsulation of paclitaxel and campothecin in aqueous liposomal formulations called Taxosomes and Camposomes , respectively. 

Camptothecin analogs Irinotecan Topotecan Epipodophyllotoxins Etoposide Teniposide Antitumor antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mitomycin Mitoxantrone Valrubicin Microtubule agents Docetaxel Paclitaxel Vinblastine Vincristine Vinorelbine Enzymes Asparaginase Pegasparaginase Metals... 

In this chapter, an attempt has been made to present a total of 30 QSAR models on 17 different heterocyclic compound series (acridine, benzimidazole, benzothiazole, camptothecin, flavonoid, indole, isatin, isoquinoUne, oncodazole, paclitaxel, phenanthridine, phenazine, podophyllotoxin, pyrrole, quinocarcin, quinoline, and quinolone) for their cytotoxic activities against various cancer cell lines. The QSARs have been found to be well correlated with a number of physicochemical and structural parameters. The most important parameter for these correlations is hydrophobicity, which is one of the most important determinants for the activity. 

This discovery significantly increased interest in the compound and led to the synthesis of a number of water-soluble analogues, which ultimately led to the development of the camptothecin analogues topotecan (Hycamtin) (15) and irinotecan (Camptosar) (16), both of which have been approved for clinical use. Topotecan is used as second-line therapy for advanced ovarian cancer in patients who have failed to respond to treatment regimens that include platinum or paclitaxel, while irinotecan has been approved for the treatment of advanced colorectal cancer. 

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