Bhashyam S. Iyengar

1,4-Disubstituted anthracene antitumor agents

Three different types of 1,4-disubstituted anthracenes were synthesized, and their cytotoxicity in a panel of tumor cells was compared with that of the corresponding 9,10-disubstituted anthracenes. The panel contained human myeloma, melanoma, colon, and lung cancer cells and sensitive and multidrug-resistant murine L1210 leukemia cells. These compounds had [[(dimethylamino)ethyl]amino]methyl, N-[(dimethylamino)ethyl]carbamoyl, and carboxaldehyde (4,5-dihydro-1H-imidazol-2-yl)hydrazone side chains. The 1,4-diamide was more potent across the tumor panel than the corresponding 9,10-isomer, but the 1,4-diamine and the 1,4-hydrazone were less potent than their 9,10-isomers. Although the 1,4-hydrazone was active against P388 leukemia in mice, it was inactive against L1210 leukemia. Within each pair of compounds, the one with greater average potency against tumor cells gave a greater increase in the transition melt temperature of DNA.

Cardiotoxicity of mitomycin A, mitomycin C, and seven N7 analogs in vitro.

SummaryThe alkylating antitumor agents mitomycin A (MMA), mitomycin C (MMC), and sevenN7 analogs were compared in terms of their cardiotoxic and antitumor activity in vitro. Neonatal rat-heart myocytes were sensitive to five of the compounds studied, including MMA, 7-dimethylamidinomitosane (BMY-25282), 7-(N-methyl-piperazinyl)-mitosane (RR-194),N7-(4-iodophenyl)-MMC (RR-208), andN7-(4-hydroxyphenyl)-MMC (M-83) in order of descending molar potency. MMA and RR-208 possessed the greatest cytotoxic potency against 8226 human myeloma tumor cells in vitro. Two of the nine mitomycins studied, BMY-25282 and M-83, showed greater cytotoxic potency for heart cells. For these two agents, the ratio of the 50% inhibitory concentration in heart cells to that in 8226 myeloma cells was 50 and 32, respectively. For the other analogs, the tumor-cell cytotoxic potency was much higher (ranging from 200 to 7,000). For the nine mitomycin compounds, a correlation was found between heart-cell toxicity and low reduction potentials (E1/2 values) ranging from −0.16 to −0.37 V. Thus, as the reduction potential decreased (easier reducibility), the cardiotoxic potency in vitro increased (r = 0.81). In contrast, mitomycins with reduction potentials of higher than −0.37 V were much less potent cardiotoxins. Thus, mitomycin C (E1/2 = −0.45 V) was noncardiotoxic even when tested at concentrations 100-fold above those pharmacologically achievable in humans. Mitomycin C also failed to enhance doxorubicin (Adriamycin) cardiotoxicity in vitro. Importantly, no correlation was found between the reduction potential and the antitumor activity of the nine analogs (n = 0.51), in this small series.

Synthesis of Mitomycins

This chapter describes mitomycin syntheses published in the period 1984–1988 plus 1989 literature available by August 1. Mitomycin synthesis was intensively investigated in this period. It is characterized by a considerable variety of strategies and novel chemistry. The most significant accomplishment was an efficient new total synthesis of mitomycin С by way of isomitomycin A. Other achievements include syntheses of decarbamoyl 7-methoxymitosane by electrophile-initiated biscyclization and by a copper-catalyzed double cyclization of an azidoquinone. New methods for 9,9a-dihydromitosenes were based on photocyclization of a diene-bearing azidoquinone and on intramolecular Reformatsky or Wittig reactions. A stereoselective synthesis of a 1,2-aziridinomito- sene involved photochemical oxidation-reduction followed by palladium-catalyzed cyclization. Mitosenes were prepared by a variety of strategies including triazole photolysis, “criss-cross” annulation of a 2-[2-(l,3-dioxocyclopentanyl)]aniline, Madelung synthesis, and Dieckmann cyclization of a substituted pyrrolazene. Other approaches were based on thermal isomerization of a 1-(1-pyrrolidinyl)-2-vinylbenzene, palladium-catalyzed cyclization of a 6-allyl-5-allylamino-1,4- benzoquinone, and intramolecular cycloaddition of a nitrile oxide to a vinyl group. A 1,2- cyclopropano derivative was formed by 1,3-dipolar addition of a diazo group to an alkene, followed by elimination of nitrogen.

Biologic Activity of a Nucleotide Conjugate Between Mitomycin C and Cytarabine Monophosphate

Abstract A dual prodrug conjugate between the antimetabolite cytarabine monophosphate and the alkylating agent 2,7-diaminomitosene (derived from mitomycin C), cytaramycin, was synthesized and tested for antileukemic activity in sensitive and resistant tumors. The compound was active against parental L-1210, CCRF-CEM, HL-60 and K-562 leukemia cells but did not overcome resistance in sublines developed for (1) multidrug resistance (L-1210/MDR and K-562-R) or (2) for cytarabine resistance (CCRF-CEM/ARA-C and HL-60/ARA-C). Alkaline DNA elution tests demonstrate a predominance of strand breaking activity due to the cytarabine moiety, and a lesser degree of DNA crosslinking, due to the mitosene moiety. The conjugate was active in mice bearing P-388 leukemia (80% increased lifespan), but was not more effective than mitomycin C alone in mice bearing a cytarabine-resistant L-1210 cell line (38% to 31% increased lifespan). These findings suggest that mitomycin nucleotide conjugates do not overcome resistance to the...

Synthesis of methyl 2,3,6-trideoxy-3-(dimethylamino)-β-L-xylo-hexopyranoside

Abstract The title amino sugar was synthesized in six steps from methyl 4,6-O-benzylidene-2,3,-dideoxy-3-trifluoroacetamido-α- d -arabino-hexopyranoside in a route based on Hortons synthesis of 3-amino-2,3,6-trideoxy sugars, but modified to avoid the problem of anhydro bridge formation. This modification was successful and all steps in the synthesis, except the final catalytic reduction, went cleanly in good to excellent yields.