Nitrogen compounds cytotoxicity

The aerial part of Zanthoxylum inerme was divided into bark and wood. From the bark, more than 0.07% of nitidine was isolated together with other related alkaloids. By contrast, none of these alkaloids were found in the wood, and 4-methoxy-l-methyl-2-quinoline was the only nitrogeneous compound occurring together with several coumarins and lignans. These results are shown in Table 5.2.2 (75). Nitidine has been shown to have cytotoxic and antitumor activities. 

The adventitious discovery of the antitumor action of the nitrogen mustard poison war gases led to intensive investigation of the mode of action of these compounds. In brief, it has been fairly well established that these agents owe their effect to the presence of the highly reactive bis(2-chloroethyl)amine group. The cytotoxic activity of... 

The nitrogen mustards are cytotoxic chemotherapy agents which are chemically derived from mustard gas. Although their current use is medicinal, the predecessor of these compounds was also used for chemical warfare putposes. 

Other studies performed on cytotoxic-Ex, like compound 126 (Eig. 20) [219-222], have revealed that the toxic effect is related to molecular LUMO energy, hpophilicity (theoretically calculated) and MulHken charge on Fx 2-nitrogen [236]. A tentative mechanism of cytotoxicity was proposed using this correlation. 

Moustafa and Ahmed reported the synthesis of isoxazoles [92,93]. These compounds are related to pyrazoles except that an oxygen replaces the amine nitrogen. Scheme 49 shows the synthesis of 182 from the corresponding chal-cone 183 by reaction with hydroxylamine. Although these compounds were not tested for cytotoxicity as tubulin binders, they were found to possess antibacterial and anti-fungal activity. 

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. 

The nitrogen mustards, compounds that incorporate a few-chloroethylamino moiety, have a venerable history as cytotoxic agents used in cancer chemotherapy. 

Another structurally related series is the 2-ary 1-1,8-naphthyridin-4-ones (37 to 48, see Table 6.7), which contain a second nitrogen in the aromatic A ring. Compounds with meta-substituted phenyls (methoxy-, chloro-, or fluoro-) or a-naphthyl groups at the C-2 position showed potent cytotoxicity in the NCI 60 human tumor cell line panel with GI50 values in the low micromolar to nanomolar range (Tables 6.7 and 6.8).51 The tumor cell line selectivity varies with the various substituents. 2-(3 -Methoxyphenyl)-naphthyridinone (37) was significantly more cytotoxic in several cancer cell lines than the corresponding 2-(3 -meth-oxyphenyl)-quinolone (36). Both compound classes were potent inhibitors of tubulin polymerization the 2-ary 1-1,8-naphthyridin-4-ones had activity nearly comparable with those... 

The cited prior art reference discloses that the compounds of formula II have significant cytotoxic and anticancer activity, which is attributed to the nitrogen mustard moiety since the reference also discloses that hydroxyl groups in the place of the... 

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