Alfred R. Crosswell

Synthesis and antitumor evaluation of water soluble taxol phosphates

Abstract Synthesis and in vivo antitmor evaluation of water soluble 2′- and 7-taxol phosphates is reported. These derivatives were found to be poor prodrugs of taxol based on their marginal in vivo antitumor activity against ip,ip M109 murine tumor model and taxol release studies in vitro .

Preclinical antitumor activity of orally administered platinum (IV) complexes

Several novel platinum (IV) mixed ammine/amine dicarboxylate dichlorides of general structure [Pt(IV)Cl2 (OCOY)2 NH3(XNH2)], where Y is aliphatic or aromatic and X is alicyclic or aliphatic, known to be particularly well absorbed following oral administration, were evaluated by that route for their antitumor activity. Testing of the Pt(IV) derivatives took place concomitantly with i.v. administered cisplatin and carboplatin in two s.c. staged tumor models, the murine M5076 sarcoma and human A2780 ovarian carcinoma. Based upon repetitive experiments which included an evaluation of different vehicles and treatment schedules, each of the orally administered Pt(IV) dicarboxylates was reproducibly active in the M5076 tumor, producing mean maximum gross log cell kill (LCK) values of between 1.5 and 2.0, and lifespan increases, reflected by mean maximum treated/control median survival (T/C) values, of 139–151%. Cisplatin and carboplatin given i.v. yielded mean maximum LCK of 3.5 and 2.5, respectively, as well as mean maximum T/C values of 166% and 164%, respectively, in the same tumor model. The best of the derivatives in the M5076 experiments, JM-216 [ammine/cyclohexylamine diacetato dichloride Pt(IV), produced LCK values that averaged only 0.5 lower than that of carboplatin, and increases in lifespan not significantly different than that of carboplatin. Against the A2780 tumor, the Pt(IV) dicarboxylates produced individual best effects of between 0.8–1.1 LCK, based on data from two or three experiments. The mean maximum LCK values for cisplatin and carboplatin were 1.8 and 2.2 LCK, respectively. JM-225, ammine/cyclopentylamine diacetato dichloride Pt(IV), was active in two of three experiments, including one result comparable to that of carboplatin. The Pt(IV) mixed ammine/amine dicarboxylate dichlorides represent a novel class of Pt derivative capable of expressing oral antitumor activity in both murine and human tumor models.

Preclinical antitumor activity of a soluble etoposide analog, BMY-40481-30

SummaryBMY-40481-30 is a new, water-soluble derivative and probable prodrug of etoposide characterized by the presence of a phosphate group in position 4′ of the E ring of the etoposide molecule. The compound was only weakly cytotoxic in vitro and, consequently, an investigation of its antitumor activity was conducted in several murine and human tumor (xenograft) models. Etoposide was administered ip or po whereas BMY-40481-30 was given ip, po or iv. The potency of the derivative, when administered parenterally, as defined on the basis of maximum tolerated dose (MTD), was less than the parent compound on a weight (mg/kg) basis in some experiments but comparable to etoposide in other instances. Comparison at the MTD of the two compounds showed that BMY-40481-30 administered ip was as active as etoposide against ip P388 leukemia. BMY-40481-30 given iv was more active than etoposide given ip in two of five experiments versus iv P388 leukemia, but the two compounds were comparably active in the other three studies. Of particular interest was the finding that the derivative was more active than the parent compound at many of the comparable (on a mg/kg basis) dose levels of both evaluated po versus iv P388 leukemia; MTD levels were not achieved, and hence not compared, for either compound using the po route of administration. Both etoposide and BMY-40481-30 yielded comparable maximum effects against ic P388 leukemia, ic L1210 leukemia, and sc B16 melanoma, but etoposide was more efficacious versus sc M5076 sarcoma. In addition to murine tumors, the HCT-116 human colon carcinoma was tested in a subrenal capsule model in athymic (nude) mice; both compounds demonstrated similar tumor inhibitory effects. Lastly, the human lung carcinomas, LX-1 and H2981, implanted sc into nude mice, showed either equivalent sensitivity to etoposide and BMY-40481-30, or a slightly enhanced sensitivity to the parent compound, in several experiments performed. BMY-40481-30 is a novel derivative and probable prodrug of etoposide with excellent solubility in water and antitumor activity generally comparable to that of the parent compound as demonstrated in several preclinical models.

Potential non-dopaminergic gastrointestinal prokinetic agents in the series of substituted benzamides

Abstract A series of 2-substituted-4-amino-5-chloro-N-[2-diethylaminoethyl]benzamides was synthesized and evaluated for gastrointestinal motility enhancing activity in vitro (enhancement of field stimulated guinea pig ileum test) and in vivo (enhancement of rat stomach emptying). A number of compounds were shown to be potent gastrointestinal prokinetic agents yet were devoid of dopaminergic D2-receptor antagonism as shown by their inability to displace [3H]spiperone from brain membranes. The model compound 6b would be expected to have clinical use in a spectrum of upper gastroinstestinal motility disorders but without the central nervous system side effects characteristic of dopaminergic D2-receptor blockade in the brain.

Synthesis and biological activity of 3',4',5'-trihydroxy etoposide

Abstract The E-ring 3′,4′,5′-trihydroxy etoposide analog 3 of the clinical antitumor agent etoposide 1 was synthesized from the corresponding etoposide ortho-quinone 2 . This analog is twice as potent as etoposide in its ability to elicit topoisomerase II mediated DNA double strand breaks. However, our in vitro cytotoxicity assay, using human colon tumor cells grown in culture, and our in vivo P388 murine leukemia screen reveal considerable loss of potency and/or activity vis-a-vis etoposide.

Synthesis and antileukemic activity of etoposide a-ring analogs

Abstract The A ring of the clinical antitumor agent, etoposide, was opened to a protected 6,7-diphenol which was derivatized to form a number of new analogs. These compounds displayed activity inferior to etoposide when evaluated against several tumor cells line in vitro and against murine P388 leukemia in vivo .

Synthesis of biological evaluation of 4′-deshydroxy-4′-methyl etoposide and teniposide analogs

Abstract The E-ring 4′-deshydroxy-4′-methyl analogs of the clinical antitumor agents etoposide and teniposide were synthesized from the corresponding 4′-triflates. These compounds display significant antitumor activity against murine P388 leukemia in vivo but are only 1/5 as cytotoxic against a human colon tumor cell line (HCT-116) grown in culture. These analogs also show inferior activity vis-a-vis etoposide and teniposide when evaluated for their ability to inhibit purified human topoisomerase II.

Novel polyamide inducers of HL-60 cellular differentiation

Abstract Four polyamides based on the structure of spermine and spermidine were prepared and tested in vitro in an HL-60 cell differentiation assay. Their activity was compared with that of hexamethylene bisacetamide (HMBA) 1 whose optimal activity (ca. 65% differentiation) is at its IC 50 of 4 mM. Triamides 7 and 13 were as good as or superior to 1 at concentrations (16 mM) which were below their IC 50 s.