azaguanine and Carcinoma--Squamous-Cell

The synthesis of 2-fluoro-8-azaadenosine (6e) and 2-amino-8-azaadenosine (6d) is described. Condensation of 9H-2,6-bis(methylthio)-8-azapurine (4) with 2,3,5-tri-O-acetyl-D-ribofuranosyl chloride (5) produces a mixture of 6a (9-beta-D-ribofuranosyl) and 7a (8-beta-D-ribofuranosyl). Standard functional group manipulation, including a modified Schiemann reaction to introduce the fluorine, allows preparation of 6d and 6e from the major isomer 6a. By a similar series of reactions the minor component 7a was converted to 7d and 7e, with the ribose ring attached at N-8 of the 8-azapurine ring system. Structure proofs utilized UV and 1H and 13C NMR data. Compounds 6b-e,g and 7b-f were evaluated in the H.Ep.-2 cell culture screen, and compounds 6c-e and 7d were evaluated in the P388 mouse leukemia screen. Adenosine deaminase data are also presented for some compounds.

Topics: Adenosine; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line; Drug Evaluation, Preclinical; Humans; Indicators and Reagents; Laryngeal Neoplasms; Leukemia P388; Leukemia, Experimental; Magnetic Resonance Spectroscopy; Mice; Spectrophotometry, Ultraviolet; Structure-Activity Relationship

The effects of 6-thioguanine on purine biosynthesis and cell viability have been examined in H.Ep. 2 cells grown in culture. Toxicity is not reversed by aminoimidazolecarboxamide, suggesting that inhibition of purine biosynthesis de novo is not the sole mechanism of toxicity. Also, 6-(methylmercapto)purine ribonucleoside, a potent inhibitor of purine biosynthesis de novo, produces more marked reductions in cellular pools of purines than does 6-thioguanine without killing cells. There is no apparent inhibition by 6-thioguanosine 5'-monophosphate of other enzymes leading to the synthesis of guanosine 5'-triphosphate as determined in whole cells by measurements of radioactive hypoxanthine or guanine incorporation. Inhibition of DNA synthesis by 1 mM thymidine protects cells from 6-mercaptopurine or 6-thioguanine but fails to protect cells from 8-azaguanine toxicity. On the other hand, inhibition of RNA synthesis by 6-azauridine plus deoxycytidine protects cells against 8-azaguanine but does not protect against 6-thioguanine or 6-mercaptopurine toxicity. In agreement with the in vitro data, arabinosylcytosine (a potent inhibitor of DNA synthesis) fails to protect mice against 8-azaguanine but has previously been shown to protect mice from 6-mercaptopurine or 6-thioguanine toxicity. The results support the hypotheses of others that incorporation into DNA (as 6-thioguanine nucleotide) is a mechanism of toxicity for these thiopurines, whereas 8-azaguanine is toxic due to its incorporation into RNA.

Topics: Azaguanine; Azauridine; Carcinoma, Squamous Cell; Cell Line; Cell Survival; Cytarabine; Deoxycytidine; DNA, Neoplasm; Guanine; Hypoxanthines; Imidazoles; Mercaptopurine; Methylthioinosine; Purines; RNA, Neoplasm; Thioguanine; Thymidine

Topics: Adenoviridae; Animals; Autoradiography; Azaguanine; Carcinoma, Squamous Cell; Cell Fusion; Cell Line; Cell Transformation, Neoplastic; Cricetinae; Dactinomycin; Deoxyuridine; Inclusion Bodies, Viral; Laryngeal Neoplasms; Mitomycins; Parainfluenza Virus 1, Human; Phenylalanine; Puromycin; Thiouracil; Thymidine; Tritium; Virus Replication

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Aza Compounds; Azaguanine; Carcinoma, Squamous Cell; Cell Line; Cells, Cultured; Drug Resistance; Humans; Hypoxanthines; Imidazoles; Inosine; Leukemia L1210; Mercaptopurine; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Pentosyltransferases; Phosphotransferases; Purines

Topics: Adenine; Animals; Azaguanine; Carbon Isotopes; Carcinoma, Squamous Cell; Culture Techniques; DNA, Neoplasm; Female; Formates; Hydroxyurea; Hypoxanthines; Leucine; Leukemia L1210; Male; Mice; Neoplasm Proteins; Oxidoreductases; RNA, Neoplasm; Thymidine; Tritium; Uridine

Topics: Alkaline Phosphatase; Aminopterin; Azaguanine; Bromodeoxyuridine; Carcinoma, Squamous Cell; Cell Line; Chromosomes; Clone Cells; Culture Techniques; Enzyme Induction; Humans; Mercaptopurine; Mouth Neoplasms; Sulfhydryl Compounds

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Azaguanine; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Headache; Japan; Leukopenia; Middle Aged; Mitomycin; Neoplasms; Nitrogen Mustard Compounds; Prognosis; Skin Neoplasms; Toxicology; Uracil Mustard