Antitumor candidate

There are numerous examples of intramolecular Heck reactions,151 such as in Entries 10 to 14. Entry 11 is part of a synthesis of the antitumor agent camptothecin. The Heck reaction gives an 11 1 endocyclic-exocyclic mixture. Entries 12-14 are also steps in syntheses of biologically active substances. Entry 12 is part of a synthesis of maritidine, an alkaloid with cytotoxic properties the reaction in Entry 13 is on a route to galanthamine, a potential candidate for treatment of Alzheimer s disease and Entry 14 is a key step in the synthesis of a potent antitumor agent isolated from a marine organism. 

Scheme 10.14 gives some other examples of Wolff rearrangement reactions. Entries 1 and 2 are reactions carried out under the classical silver ion catalysis conditions. Entry 3 is an example of a thermolysis. Entries 4 to 7 are ring contractions done under photolytic conditions. Entry 8, done using a silver catalyst, was a step in the synthesis of macbecin, an antitumor antibiotic. Entry 9, a step in the synthesis of a drug candidate, illustrates direct formation of an amide by trapping the ketene intermediate with an amine. 

Further investigations revealed that the superior antitumor efficacy of Leu-DOX was, indeed, due to site-selective activation and delivery of doxorubicin. At equitoxic intravenous doses of DOX and Leu-DOX (8 and 28 mg/kg, respectively, see above), the plasma levels of DOX attained were comparable, whereas differences were seen in tumor tissue concentrations [51]. The enzymes involved in the tumor-selective activation of Leu-DOX were not identified, although possible candidates include the cathepsin family of proteases [47],... 

Turning our attention first to alkyl carbamates of cyclic amides, we find interesting attempts to improve the pharmaceutical and pharmacokinetic properties of 5-fluorouracil (8.152, R = H) [194-196], This antitumor agent, while clinically useful, suffers from poor water solubility, unsatisfactory delivery properties and low tissue selectivity. A variety of prodrug candidates were prepared, in particular the alkyl and aryl carbamates presented in Table 8.12. With the exception of the more-lipophilic derivatives, these compounds exhibited somewhat improved water solubility. More importantly, both rectal and oral bioavailability were markedly improved. The activation... 

ZD6474 is one of the many immunomodulating molecules currently in clinical trials for the treatment of various types of cancers. Its aqueous solubility (330 (xM at pH 7.4) and antitumor activity at a dosage as low as 12.5 mg/kg per day in mice made this compound a good candidate for clinical trials in replacement of the more potent but less bioavaUable analog ZD4190. 

The resolution of the hydroxyglycine derivative 12 was required as the intermediate in the synthesis of a clinical trial candidate for an immunosuppressive agent and antitumor compound (-)-15-deoxyspergualin (14) (Scheme 7.7). The lipase from... 

The high affinity of many platinum compounds for sulfur and the availability of many sulfur-containing biomolecules have raised the question whether Pt-sulfur biomolecule interactions could serve as a drug reservoir for platination at DNA, necessary for the antitumor activity of cis-Pt. Two reaction paths are possible, i.e., spontaneous release of plantinum from the sulfur, or nucleophilic displacement of platinum from sulfur by guanine (N7), for example. At the moment, there is no real evidence for the existence of such reactivation mechanisms. In fact, it has been reported that Pt-protein interactions in the plasma (albumin) are not reversible under normal conditions (161, 165). Further, a mixture of cis-Pt-methionine products does not show antitumor properties (166), indicating no induced platination of DNA. More research is required to investigate the existence of a reactivation mechanism. However, it is predicted that if such a reactivation phenomenon is operational, the most likely candidate is the labile Pt-methionine bond, as has been shown by its rapid reaction with Naddtc, STS, and thiourea (vide supra) (131). 

Some of these cytotoxic marine alkaloids are promising candidates for new drugs. For example, ecteinascidins, Fig. (29) are a family of tetrahydroisoquinolone alkaloids isolated from the Caribbean tunicate Ecteinascidici turbinata, which have been selected for clinical development. These compounds are presently in pre-clinical and clinical trials for human cancers [221-225], A series of totally synthetic molecules that are structurally related to the ecteinascidins is currently being prepared and evaluated as antitumor agents [226],... 

Although historically most useful antibiotics have come from spore forming microorganisms, marine organisms have yielded the candidate antitumor peptide dideinnin B and cytostatic peptides such as the patellamides. Many of the marine peptides have little or no antimicrobial... 

The Mechanism of the Reduction of (ImH)[trans-RuCl4(dmso)(Im)i by Ascorbic Acid Antitumor activity of metal complexes is not restricted to those of Pt (II) cited earlier. Some recent reports of possible candidates for the purpose of functioning as substitutes for the Pt(II) range of complexes have included Pd(II)... 

Welwistatin also inhibits cell proliferation with reversible depletion of cellular microtubules in ovarian carcinoma cells and A-10 vascular smooth muscle cells by inhibiting the polymerization of tubulin, but it does not alter the ability of tubulin to bind [3H]colchicine or to hydrolyze GTP [8]. Due to the cytotoxicity associated with the inhibition of tubulin polymerization, which is the main mechanism of action of antitumor drugs such as vincristine and vinblastine, and because P-gp-overexpressing cells show virtually no resistance to welwistatin due to its MDR reversal properties, this natural product could be a good candidate in the chemotherapy of drug-resistant tumors. 

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