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Synthesis of the epimer of pericosine B from (-)-quinic acid was achieved. This synthesis involves some regioselective and stereoselective processes. The desired product showed lower cytotoxic activity in comparison with natural pericosine B against the P388 leukemia cell line. The result implies that the stereocenter of C-6 in natural pericosine B plays an important role in this activity.

Two new pregnane alkaloids, wrightiamines A (1) and B (2), were isolated from the extract of the tropical Apocynaceous plant Wrightia javanica collected in Thailand, and their structures were elucidated by spectral data. Wrightiamine B (2) was preparaed from 3beta-hydroxy-5alpha-pregnan-20-one to establish the configuration of the C-20 position as S. Wrightiamine A (1) exhibited cytotoxic activity against vincristine-resistant murine leukemia P388 cells.

Indolo[3,2-b]quinoline derivatives (1b-i) with a methyl group at each possible position have been synthesized. The 1-methyl (1b) and 9-methyl (1i) derivatives were inactive, but the 3-methyl (1d), 4-methyl (1e), and 6-methyl (1f) derivatives exhibited high treatment/control (T/C) value and cure rates against leukemia P388 in mice. These results indicated that modification of indolo[3,2-b]quinoline derivatives at 3, 4, and 6 positions may be useful approach for lead optimization.

Various kinds of water-soluble quaternary salts of 2-(2'-oxoalkoxy)-9-hydroxyellipticines were synthesized in a search for compounds with potent antitumor activity and low toxicity. Some compounds exhibited more potent antitumor activities than elliptinium (1) and SUN 4599 (3). In particular, 2-(3'-methoxy-2'-oxopropanoxy)-9- hydroxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazolium bromide (4d) showed potent antitumor activities against P388 leukemia, colon 26, and Lewis lung carcinoma.

Five new chlorinated phenyl ethers, russuphelins B (2), C (3), D (4), E (5) and F (6) have been isolated from the mushroom Russula subnigricans Hongo, and their structures were elucidated by spectroscopic and chemical means. Russuphelins B (2), C (3) and D (4) exhibited cytotoxic activity in vitro against P388 leukemia cells.

Novel indolo[3,2-b]quinolines (1b-k), having a nitro, amino, acetamido, methanesulfonamido, or glycosylamino group at the 2, 7, or 8-position, were prepared and their antitumor activities against P388 leukemia in mice were examined. The 7-galactopyranosylamino derivative (1g) showed the most potent activity (optimal dose = 25 mg/kg, T/C greater than 333%, cure rate 5/6).

Seventy novel benzoylphenylurea compounds were synthesized and their antitumor activities were examined in vivo against P388 leukemia. N-(2-Nitrobenzoyl)-N'-[4-(2-pyrimidinyloxy)phenyl]ureas showed the highest antitumor activities when dosed intraperitoneally or orally. Their structure-activity relationships were examined with particular focus on the position and the variety of subsitituent on each aryl ring.

Novel indolo[3,2-b]quinolines (1d-g), introduced at the 7-position with an N-glycosylamino group, were prepared and their antitumor activities against leukemia P388 in mice were examined. The N-Galactopyranosylamino derivative (1e) was a much more potent anti-leukemia compound (optimal dose = 25 mg/kg, T/C greater than 333%, cure 5/6) than lead compound 1a.

Poly(L-lactic acid) (L-PLA) microspheres containing 5-fluoro-2'-deoxyuridine (FUdR) or its ester prodrugs with saturated aliphatic acids (FUdR-Cn, n = 2, 3, 4, 5, 6, 8, 10 and 12) were prepared. The physicochemical and biological properties and antitumor activity of the L-PLA microspheres were studied. The lipophilicity of FUdR-Cn was increased by prolonging its acyl-promoieties. FUdR-C5, FUdR-C6, FUdR-C8, FUdR-C10 and FUdR-C12 showed almost complete incorporation into the microspheres, while incorporation of hydrophilic FUdR and FUdR-C2 was poor. The sustained release of FUdR from the microspheres containing FUdR-C4, FUdR-C5 and FUdR-C6 was obtained in the presence of esterase, and higher antitumor activity against P388 leukemia was observed in vivo. On the other hand, the release rates of FUdR from the microspheres containing FUdR-C10 and FUdR-C12 were very small, and their antitumor activity was much smaller than that of the free prodrug suspension. Effects of the susceptibility to enzymatic hydrolysis and the physiocochemical properties of prodrugs on the release profiles of FUdR from spheres were discussed.

In order to study a new antitumor platinum complex, various platinum complexes were prepared from 2-amino-methylpyrrolidine derivatives synthesized to serve as carrier ligands and tested for their antitumor activity against Colon 26 carcinoma (s.c.-i.p. system) and P388 leukemia (i.p.-i.p. system) in mice. 2-Aminomethylpyrrolidine proved to be the most effective carrier ligand in its amine derivatives. The structure-activity relationships of the carrier ligands in the platinum complexes with dichloro, oxalato, 1,1-cyclobutanedicarboxylato and dichlorodihydroxo as leaving group were clearly shown on the Colon 26 carcinoma screen and were as follows: the antitumor activity of the platinum complexes with any leaving groups was considerably decreased by the substitution of hydrogen by alkyl group (Me, Et) on nitrogen of aminomethyl and the effects of 1,1-cyclobutanedicarboxylato Pt(II) complexes completely disappeared with the same substitution on nitrogen of pyrrolidine. In all the tested platinum complexes 2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)platin um(II) (15) exhibited the most potent antitumor activity. 15 was superior to 1,1-cyclobutanedicarboxylatodiammineplatinum(II) (CBDCA) and similar to cis-diamminedichloroplatinum(II) (CDDP) on the Colon 26 carcinoma screen but it was inferior to CBDCA and CDDP on the P388 leukemia screen. Furthermore, 15 showed more potent antitumor activity than CBDCA against Colon 38 carcinoma (s.c.-i.p. system).

Phospholipase D from Streptomyces effectively catalyzed the transfer reaction of the phosphatidyl residue from 3-sn-phosphatidylcholine to the 5'-hydroxyl group of nuclesides in a two-phase system. Thus, a variety of 5'-(3-sn-phosphatidyl)nucleosides could be readily prepared in high yields by means of this reaction. Among them, phosphatidyl-FUR (3b), phosphatidyl-Ara FC (8b), and phoshatidyl-neplanocin A (12b) each produced a significant increase in the life span mice bearing i.p.-implanted P388 leukemia, being more effective than the parent nucleosides.

Par action de la β-thujaplicine (A) sur l'ethoxy-1 isochromanne, synthese de l'hydroxy-2 [isochromannyl-1]-3 isopropyl-6 heptatrienone; etude de son O-methylation par le diazomethane. Par action de A sur le diethylacetal du benzaldehyde, synthese de l'α-ethoxybenzyl-3 hydroxy-2 isopropyl-6 cycloheptatrienone et de la dihydroxy-2,2' diisopropyl-6,6' α-phenyl methylene-3,3' bis-cycloheptatrienone. Activites anticancereuses in vitro et in vivo chez la souris des composes prepares

Antitumor agents of a new structural type are reported. A number of cyanines with mono-, di- and tricyclic nuclei, merocyanines and oxonols have been i. p. screened for antitumor activity against P388 leukemia and B16 melanoma. Among these compounds, monomethin-, trimethin- and pentamethincyanines having naphthothiazole, naphthoxazole and benzindole nuclei resulted in a significant prolongation of the survival time of tumor-bearing mice. Replacement of the conjugated chain system between the terminal two nuclei with a saturated aliphatic chain produced a marked decrease in the antitumor activity. Structure-activity relationships are discussed.