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CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models.

A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has been identified from its parent, the novel antifungal agent RO0094815 (2). The prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which undergoes enzymatic activation followed by spontaneous chemical degradation to release 2. Prodrug 1 showed high chemical stability and water solubility and exhibited strong antifungal activity against systemic candidiasis and aspergillosis as well as pulmonary aspergillosis in rats.

Water soluble N-benzyltriazolium or N-benzylimidazolium salt type prodrugs of several highly lipophilic triazole or imidazole antifungals have been synthesized. They were designed to undergo an enzymatic activation followed by a self-cleavage to release a parent drug. The prodrugs such as 16 had enough chemical stability and water solubility for parenteral use and were rapidly and quantitatively converted to the active substance in human plasma.

N4-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390), a new prodrug of 5'-deoxy-5-fluorouridine (5'-dFUrd), was synthesized for the purpose of finding a drug with less intestinal toxicity than the parent compound. The present study compared the antitumor activity and immunotoxicity of Ro 09-1390 with those of 5'-dFUrd, 5-fluorouracil (5-FUra) and tegafur in various transplantable tumor models. The antitumor efficacy of Ro 09-1390 was comparable to 5'-dFUrd and these two agents were much more effective than the others. However, Ro 09-1390 was much less toxic to the intestinal tract and less immunosuppressive in both humoral and cellular immune reactions than 5'-dFUrd. Consequently, Ro 09-1390 showed higher therapeutic indices and higher efficacy than 5'-dFUrd at high dosages. The antitumor spectrum of Ro 09-1390 was somewhat different from that of 5'-dFUrd, though it shows the efficacy after it converts to 5'-dFUrd. The activity of Ro 09-1390 was partly associated with cytidine deaminase in the tumors treated. Ro 09-1390 appeared to be more effective against tumors with a high concentration of the enzyme by which the major metabolite 5'-deoxy-5-fluorocytidine (5'-dFCyd) is metabolized to 5'-dFUrd.

N4-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390), a prodrug of the cytostatic 5'-deoxy-5-fluorouridine (5'-DFUR), was synthesized with the aim of reducing of the dose-limiting toxicity of 5'-DFUR, which is diarrhea. In mice bearing Lewis lung carcinoma, 5'-DFUR given po produced a substantial amount of 5-fluorouracil (5-FU) in the intestinal tract as well as tumors, where the enzyme pyrimidine nucleoside phosphorylase, essential for conversion of 5'-DFUR to 5-FU, is predominantly located. With the oral administration of Ro 09-1390 only a small amount of 5-FU was formed in the intestine; however, the administration of Ro 09-1390 and 5'-DFUR at the same dose produced similar amounts of 5-FU in tumor tissues. These differences in metabolism were reflected in their toxicity and antitumor efficacy. The administration of 5'-DFUR resulted in damage to the intestinal mucosal membrane and diarrhea in normal mice, whereas Ro 09-1390 was much less toxic to the intestinal tract. As regards antitumor activity, Ro 09-1390 and 5'-DFUR at equivalent doses inhibited the growth of Lewis lung carcinoma to similar extents. Since Ro 09-1390 was much less toxic to the intestinal tract than 5'-DFUR, mice bearing Lewis lung carcinoma could be given Ro 09-1390 daily over a longer period and at a higher dose, resulting in a longer survival time.