Antitumor activity action

The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis whereas RNA synthesis is not affected (261). The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. The mechanism of action of maytansine (104) has been hypothesized to be the acid catalyzed loss of water from the C-9 hydroxyl group of the carbinolamide to form a reactive acyl imine intermediate, which reacts rapidly with nucleophiles on the bases of DNA (262). 

The novel agent sulofenur (69) has entered clinical trials based on its broad spectmm antitumor activity in tumor models, its unusual mechanism of action, and its lack of cross-resistance to other agents (33). In Phase I clinical trials, the dmg was well tolerated and some clinical responses were noted. 

Indeed, the observation that vanadate is a potent inhibiter of phosphate-recognizing enzyme systems was a great stimulus to work in this area, but it now seems likely that its action is more complicated than simple mimicry of phosphates.This is germane to obtaining an understanding of the antitumor activity of [V( j -C5H5)2Cl2]. 

Azinomycins A and B (64 and 65 Scheme 11.5) [115, 116] were isolated in 1986 from Streptomyces griseofuscus at the SS pharmaceutical company in Japan and were found to have potent in vitro cytotoxicities [117] and to display significant in vivo antitumor activity [118]. Since their discovery [117] and structure determination [119], their unusual molecular framework has attracted the attention of many chemists interested in their mode of action and in developing synthetic approaches to them [115,116]. The first total synthesis of azinomycin A was achieved in 2000 by Coleman et al. [120]. 

Interferon-a2b has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity.42 The antitumor activity is due to a combination of direct antiproliferative effect on tumor cells and indirect immune-mediated effects.42 Interferon-a2b is currently approved by the Food and Drug Administration (FDA) as adjuvant therapy for patients who are free of disease after curative surgical resection but are at high risk of MM recurrence. This includes patients with bulky disease or regional lymph node involvement such as stage IIB, IIC, or III disease.43 It is controversial if interferon-a2b (IFN) should be offered as adjuvant therapy for every high-risk MM patient. The reason is because clinical trials with different doses of IFN have not proved definitively that IFN improves overall patient survival. 

Das has described the cycloaddition of camptothecin (92), an alkaloid with potent antitumor activity, with maleic anhydride under the action of microwave irradiation in a commercial microwave oven for 9 min [78]. Two unprecedented adducts, 93 and 94, were produced. The first was formed by involvement of the B-ring in a hetero Diels-Alder reaction whereas the second was formed by involvement of the C-ring, probably through Diels-Alder reaction of intermediate 95 (Scheme 9.28). 

As a logical step in studies of the antiproliferative action of pool components in tumor cells we studied the antitumor activity of peptides in combination with standard antitumor chemotherapeutic agents (vincristin, metatrexate, cis-platin, epirubicin) [48]. 

The mechanism of biological action of 281 has been thoroughly investigated (04MI4, 04MI5). These 2-aminochromenes reveal anticancer activity as the result of caspase activation, and, consequently, starting the apoptosis mechanism. However, somewhat different 2-amino-4H-chromenes 161 show antitumor activity by another mechanism, which involves inactivation of antiapoptotic proteins of the Bcl-2 series. 

Chlorambucil (Leukeran) is an aromatic nitrogen mustard that is intermediate in chemical reactivity between mechlorethamine and melphalan. Its mechanisms of action and range of antitumor activity are similar to theirs. It is well absorbed orally, but detailed information concerning its metabolic fate in humans is lacking. 

The biosynthesis 237,5381 involves enzymatic dehydration of serine and threonine residues in a manner similar to the formation of thiazoles and dihydrothiazoles vide supra) with or without subsequent oxidation to yield the 2-(l-aminoalkyl)oxazole-4-carboxylic acid and 2-(l-aminoalkyl)dihydrooxazole-4-carboxylic acid shown in Scheme 38. These cyclic peptides display interesting physiological properties such as cytotoxicity/541, 569,5831 antitumor activities, or antineoplastic effects/523,5291 but as for the sulfur-containing compounds the mechanism of action is not yet understood despite extensive SAR studies. 515,521,540,5431... 

The first, in vivo study on the antitumor activity of ketonucleosides appeared14 in 1977. The action of l-(6-deoxy-2,3-0-isopropylidene-a-L-h/xo-hexopyranosyl-4-ulose)thymine (45) and of 7-(3-0-acetyl-4,6-dideoxy-/ -L-gfi/cero-hex-3-enopyranosyl-2-ulose)theophylline (61a) against LI 210 leukemia in mice was examined comparatively. From the results obtained, it was clear that the unsaturated ketohexosylpurine 61a was much more active than the ketohexosylpyrimidine 45, whereas the parent nucleosides (44 and 34a, respectively) were inactive under the same experimental conditions. 

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