Antineoplastic activity

S. antimycoticus Antinematodal activity Antineoplastic Antineoplastic activity Antineoplastic agent... 

The phleomycin, bleomycin and related families are widespectrum antibiotics containing the pyrimidine (987) in addition, they have antineoplastic activity and bleomycin is already in clinical use for certain tumours. They were isolated about 1956 from Streptomyces verticillus, and in addition to the pyrimidine portion the molecules contain an amide part (R ) and a complicated part (R ) consisting of polypeptide, an imidazole, two sugars, a bithiazole and a polybasic side chain which can vary widely phleomycin and bleomycin differ by only one double bond in the bithiazole section (78MI21303). The activity of such antibiotics is increased by the addition of simple heterocycles (including inter alia pyrimidines and fused pyrimidines) and other amplifiers (82MI21300). 

Uracil is used more effectively, in nucleic acid synthesis within a rat hepatoma than in normal liver. This observation appears to have stimulated the synthesis of 5-fluorouracil (1027) as an antimetabolite mainly because the introduction of a fluorine atom involves a minimal increase in size. In the event, 5-fluorouracil did prove to have antineoplastic activity and it is now a valuable drug for treatment of tumors of the breast, colon or rectum, and to a lesser extent, gastric, hepatic, pancreatic, uterine, ovarian and bladder carcinomas. As with other drugs which interfere with DNA synthesis, the therapeutic index is quite low and great care is required during treatment (69MI21301). 

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

Pyrimidinopyrazines related to folic acid have been investigated in some detail for their antimeta-bolic and antineoplastic activities. A related compound, which lacks one nitrogen atom, has been described as an antiproliferative agent, indicating it too has an effect on cell replication. Aldol condensation of the benzaldehyde 99 with ethyl acetoacetate gives the cinnamate 100. This is then reduced catalytically to the acetoacetate 101. Reaction of that keto ester with 2,4,6- triami-nopyrimidine gives the product 102 which is subsequently chlorinated (103) and subjected to hydrogenolysls. There is thus formed piritrexim (104) [17]. 

Carmustine is a bicyclohexylnitrosourea (BCNU, Fig. 3) with broad spectrum of antineoplastic activity (e.g., lymphomas, multiple myeloma, sarcomas, brain tumors, gastrointestinal tumors, melanomas). At doses of 80-200 mg/m2 it is given i.v. at 6 week s intervals. 

Thiotepa is chemically less reactive than the nitrogen mustards. It has antineoplastic activity against ovarian and breast cancers as well as lymphomas. However, it has been largely supplanted by cyclophosphamide and other nitrogen mustards. 

Lin, A. J. Shansky, C. W. Sartorelli, A. C. Potential bioreductive alkylating agents. 3. Synthesis and antineoplastic activity of acetoxymethyl and corresponding ethyl carbamate derivatives of benzoquinones. J. Med. Chem. 1974, 17, 558-561. 

A derivative of benzylhydrazine, procarbazine (8), exhibits antineoplastic activity. In an interesting insertion-type sequence, reaction of the p-toluamide (5) with ethyl azodicarboxylate leads directly to the substituted hydrazine (6). It is not unlikely that the first mole of the diazo compound... 

As described in several monographs [4], bryostatin 1 exhibits significant in vitro and in vivo antineoplastic activity against a range of tumor cell lines including murine leukemia, B-cell lymphoma, reticulum cell sarcoma, ovarian carcinoma, and melanoma. It is also effective in the modulation of apoptotic function [5], the reversal of multidrug resistance [6], and stimulation of the immune system [7]. These unique features displayed by bryostatin 1 are attributed to its high affinity for protein kinase C (PKC) isozymes and its ability to selectively modulate their functions [8]. PKCs are a type of intracellular serine and threonine kinase that... 

Wadler, S. and Schwartz, E.L., Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies A review, Cancer Res., 50, 3473, 1990. 

Cleavage of aziridines has been employed in the asymmetric total synthesis of pancratistatin 57 [47], a compound that is the object of considerable attention thanks to its broad spectrum of antineoplastic activities [48]. The chemistry of vinylaziridines has for the most part been confined to their use in rearrangement sequences resulting in functionalized pyrrolines. Hence, because of the lack of data concerning the ring-opening of vinylaziridines with carbon nucleophiles,... 

Antibiotics with antineoplastic activity continue to appear and rubidomycin (daunomycin, daunorubicin) [455] is currently receiving wide study. 

Esters of l-(4-pentyloxybenzoyl)cyclopropane-2,2,3-tricarboxylic acid 133 have antineoplastic activity. Thus oral application of 100 mg/kg per day to mice for eight days suppressed the growth of transplanted S 37 tumor by 26%, Eq. (53) [184]. 

Two derivatives of podophyllotoxin (38), etoposide (39) and tenipo-side (40), are further examples of the use of a natural product as a drug lead. In 1890, podophyllotoxin was isolated from Podophyllumpeltatum L. (American May Apple), and in 1948, it was shown to have antineoplastic activity in mice bearing tumors. Then, hundreds of podophyllotoxin... 

Diazoazoles have found wide application. Among the biological applications is the remarkable antineoplastic activity of several diazoazoles and in particular of 4-diazoimidazole-5-carboxamide. Chemical applications are extensive because of the high reactivity and versatility of the diazo/diazo-nium function. 

The Ley research group [76] developed a flow process for the multistep synthesis of ( )-oxomaritidine, an alkaloid found in the Amaryllidaceae family, known to have antineoplastic activity (Scheme 34) [77, 78]. The route does not involve intermediate purification of the products, which is necessary in the previously reported... 

The distinctive chemical structure of this drug gives it selective antineoplastic activity. Present in the blood, it is practically inactive, although upon penetrating cancerous cells... 

Antineoplastic activity of carnosine was first reported more than two decades ago (Nagai and Suda, 1986). L-Carnosine s ability to kill cultured transformed cells (3T3 cells and HeLa cells), selectively, was found to be... 

Isoguanine (94), which is found in Prioneris wings along with hypoxanthine (92), xanthine (91), and uric acid (95), shows antineoplastic activities (Table VI) (57). Isolation of urocanic acid (137) from this wing material represents the first detection of this histidine derivative in an arthropod (Table VIII). A nonpteridine pigment, xanthommatin (58) (cf. Section II,B,l,b), is found in the larval body of Pieris brassicae (Table V). 

Lopez Abraham. A. N., N. M. Rojas Hernandez, and C. A. Jimenez Misas. Potential antineoplastic activity of Cuban plants. IV. Rev Cubana Farm 1981 15(1) 71-77. 

An intramolecular cycloaddition of the tetradecatrienyl nitroethyl ether 263 was used in the synthesis of the 14-membered bicyclic precursor 265 of crassin acetate 266, a cembrane lactone possessing antibiotic and antineoplastic activity (332). Nitro compound 263 was obtained from farnesyl acetate (262) in several steps and was then treated with phenyl isocyanate and triethylamine to give the tricyclic isoxazoline 264 (Scheme 6.98). Conversion to ketone 265 was accomplished by hydrogenation of the cycloadduct with Raney Ni and boric acid followed by acetylation (332). In this case, the isoxazoline derived from a 3-butenyl nitroethyl ether moiety served to produce a 3-methylenetetrahydropyran moiety (332). 

Little information on the reactivity of pyrazinooxazines was available for inclusion in CHEC-II(1996) <1996CHEC-II(7)737> and little has been published since. Ring opening of pyrazino[2,3-t/][l,3]oxazines by amines to form amides (Equation 155) has been reported, but is rather inefficient <2005W02005/115986>. As shown in Equation (156), oxidation of a benzannulated pyrazino[2,3- ][l,4]oxazine, catalyzed by iV,A -bis(salicyliden)ethylenediiminecobalt(ii) (salcomine), gives a quinonoid product, of interest for its antineoplastic activity <2001H(54)619>. 

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