P388

Leptosins D-F (258a-c, Scheme 39) [94JCS(P1)1859] were isolated by Takahashi and co-workers from the culture of a strain of Leptosphaeria sp. as cytotoxic substances against the P388 lymphocytic leukemia cell line comparable to that of mitomycin C. Utilizing the nucleophilic substitution reaction of 1-hydroxytryptamines, a simple methodology for the synthesis of core structures of leptosins has been developed (2000H1255). 

Condensation of 594 with alloxan followed by methylation of the presumably formed purino[7,8-g]-6-azapteridine gave 597. Treatment of the latter with alkylamines afforded (87CPB4031) [1,2,4]triazino[2,3-/]purines 598. Compound 597 was active against P388 leukemia. Vascular relaxing effects of 598 were determined, but none showed potent activity (87CPB4031) (Scheme 123). 

Table 6.4 Cytotoxcitiy and antitumor activity of selected gold complexes on B16 Melanocytes and P388 leukocyte. Adapted from Shaw [17].

Complex B16 Melanoma ICso (pM) in vitro P388 in vivo ILS (%) Ref. 

A copper(II) complexes of 5-phenylazo-3-methoxy salicylidene thiosemicarbazone has been shown to have promising growth inhibition activity against P388 lymphocytic leukemia cells sensitive and resistant to adriamycin [196], The complex involves ON coordination of two deprotonated ligands and v(CS) is reported to be unaltered in intensity and position in the complex from its position in the spectrum of the ligand. Inhibition studies with the uncomplexed thiosemicarbazone indicating an important role for the copper(II). 

The electronic spectra and magnetic susceptibility of [Ni(21)Cl2] were found to be consistent with a five-coordinate high spin complex. This complex has greater antitumor activity against P388 lymphocytic leukemia test system in mice than cobalt(II), copper(II), zinc(II) and platinum(II) complexes of 21 [187],... 

Although 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone, 22, also forms [Ni(22)Cl2] with chemical properties similar to [Ni(21)Cl2], it, along with other metal complexes of 22, showed no activity against P388 lymphocytic leukemia test system in mice [202]. 

A series of paramagnetic [NiL-2H] complexes have been isolated in which L = 2,6-diacetylpyridine bis(azacyclothiosemicarbazones) with Ni(II) assuming a distorted five-coordinate structure with d-d bands at about 7250, 10510, 12500, 14400, 19200 and 20500 cm [153], None of these Ni(II) complexes were reported to have activity against the P388 lymphocytic leukemia test system in mice. 

Several years ago, a collection of megapotamica found growing in a saltwater marsh near Curitioa, Brazil, was shown to contain a series of compounds which exhibited very high activity jji vivo against mouse P388 leukemia... 

Figure 1. Survival effects for chitin-5FU conjugates(l) against p388 leukemia in mice ip/ip. D5FU=8.3mol%, D5FU=llmol%, (°) 5FU.

Figure 3. Survival effect for a-l,4-polygalactosamine-5FU(3) and partially N-acetylated a-l,4-polygalactosamine-5FU(4) conjugates against p388 leukemia in mice ip/ip. Q 3(Pn=20-60 D5FU=28mol%), 3(Pn=20-60 ...

The authors wish to express their sincere appreciation to Dr. Tazuko Tashiro of Cancer Chemotherapy Center of the Japanese Foundation for Cancer Research for the screening test of the survival effect against p388 lymphocytic leukemia in mice ip/ip. 

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