David W. Henry

Adriamycin analogues. 3. Synthesis of N-alkylated anthracyclines with enhanced efficacy and reduced cardiotoxicity.

Reaction of daunorubicin (1) and adriamycin (2) with aldehydes and ketones in the presence of NaCNBH3 afforded N-alkyl- and N,N-dialkylanthracyclines along with their 13-dihydro derivatives. Product ratios depended upon the nature of the carbonyl reagent and the starting drug. The majority of these analogues retained in vivo antitumor activity comparable to 1 and 2. However, unlike the parent compounds, which inhibit DNA and RNA synthesis at comparable concentrations, several of these analogues inhibit RNA synthesis at markedly lower concentrations than required to inhibit DNA synthesis. In addition, in some cases the ability to bind to DNA in vitro was reduced while antitumor activity was retained. N,N-Dibenzyldaunorubicin was especially notable for increased efficacy (T/C 259, qd 1--9) against P388 leukemia in mice, despite reduction of DNA binding in vitro. It showed almost complete loss of mutagenicity vs S. typhimurium (Ames test) and it was tenfold less cardiotoxic by electrocardiographic measurements (Zbinden test) in the rat.

Synthetic C-nucleosides: 3-(α- and β-D-arabinofuranosyl)pyrazolo[4,3-d]pyrimidine-5,7-diones

Abstract 2,3,5-Tri- O -benzyl- D -arabinofuranosyl bromide ( 4 ) was converted into 2,5-anhydro-3,4,6-tri- O -benzyl- D -glucononitrile ( 5 ), mixed with 20% of the D - manno epimer 6 . The mixture was reduced to the amine 7 , which via the N -nitrosoacetamide 10 afforded the 1-deoxy-l-diazo sugar 11 . Dipolar addition to dimethyl acetylene-dicarboxylate afforded the C -nucleoside derivative, dimethyl 3-(2,3,5-tri- O -benzyl-α-β- D -arabinofuranosyl)pyrazole-4,5-dicarboxylate ( 20 ). Selective ammonolysis afforded the 4-ester-5-carboxamide 21 , which was separated chromatographically into the α-(minor) and β-(major) anomers. Hydrazinolysis and Curtius reaction of the pair of 4-acid hydrazides (α- 22 and β- 22 ) afforded the anomeric 3-glycosyl-1 H -pyrazolo-[4,3- d ]pyrimidine-5,7-diones (α- 24 and β- 24 ). Hydrogenolytic debenzylation yielded the β- D )- arabino epimer ( 1 ) of oxoformycin B , and the α- D - arabino form 2 . These anomeric C -nucleosides were distinguished by circular dichroism spectra that showed the same relationship as α- and β- D - arabino anomers of normal purine nucleosides.

Synthesis of the nucleoside antibiotic formycin B

Curtius rearrangement of the 4-azide of 5-(tri-O-benzyl-β-D-ribofuranosyl)pyrazole-3,4-dicarboxylic acid gave the N-carboxy-anhydride of the 4-amino-3-acid the methyl ester of which, on heating in formamide followed by catalytic hydrogenolysis, gave formycin B.

Inhibitors of histone methylation

Two classes of inhibitors of histone methyltransferase I from calf thymus are reported. High concentrations (≧ 10 mM) of various alkyl or aralkyl amines and polyamines were inhibitory to the enzyme. Spermine and spermidine were among the most potent compounds in this group. The best monoamine inhibitor was 2-phenylethylamine, which gave 47% inhibition at 10 mM. The substituted phenanthridinium compound ethidium bromide was also an inhibitor of the enzyme. A number of analogs of ethidium bromide were tested, and the most potent compound (17) gave 50% inhibition at 0.125 mM. S-Adenosyl-l-ethionine (SAM) showed competitive inhibition of the enzyme as determined from a Lineweaver-Burke plot, while ethidium bromide was noncompetitive.

Inhibition of nucleic acid synthesis in leukemia 1210 cells by antimetabolites of coenzyme Q10.

Abstract Thirteen diversified antimetabolites of coenzyme Q10 which have antitumor activity in vivo were tested for inhibition of uptake of tritiated thymidine and uridine into DNA and RNA, respectively, of L1210 cells grown in tissue culture. Eight of these antimetabolites have inhibitory activities of the same order of magnitude as the used anticancer drugs, rubidazone and ellipticine. 5-ω-Phenylpropylmercapto-2,3-dimethoxy-1,4-benzoquinone was particularly potent to inhibit nucleic acid synthesis; ED50 for DNA = 2.1 μM and ED50 for RNA = 4.0 μM.