Reference

Synthesis of potential hypolipidemic agents

Synthesis of potential hypolipidemic agents. Reaction of substituted phenyl 2,3-epoxypropyl ethers with adenine, uracil, and thymine. DiMenna, William S.; Piantadosi, Claude; Lamb, Robert G. (Sch. Pharm., Univ. North Carolina, Chapel Hill, N. C., USA). J. Med. Chem., 21(10), 1073-6 (English) 1978. CODEN: JMCMAR. ISSN: 0022-2623. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacodynamics) Section cross-reference(s): 28 Purines I (R = Br, Cl, F, MeO, Me3C, Ac, 4-BzC6H4; X = O, S) and pyrimidines II (R = Cl, Me, MeO; R1= H, Me) were prepd. in 20-65% yields by the condensation of adenine [73-24-5], uracil [66-22-8], and thymine [65-71-4] with epoxides III in Me2SO-K2CO3 at 38°. The reaction of epichlorohydrin [106-89-8] and 4-RC6H4OH in the presence of Bu3PhCH2N+Cl- gave III. I(R = Cl, X = O) [67666-70-0] significantly lowered serum triglyceride and cholesterol [57-88-5] content in male Sprague-Dawley rats and inhibited hepatic phosphatidate phosphohydrolase [9025-77-8] activity in vitro.

Repair of O6-alkylguanine during DNA synthesis in murine bone marrow hematopoietic precursors

Repair of O6-alkylguanine during DNA synthesis in murine bone marrow hematopoietic precursors. Gerson, Stanton L.; Trey, Joan E.; Miller, Kathleen; Benjamin, Evan (Univ. Hosp. Cleveland, Case West. Reserve Univ. Med. Sch., Cleveland, OH 44106, USA). Cancer Res., 47(1), 89-95 (English) 1987. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 4 (Toxicology) O6-Alkylguanine, a DNA adduct formed by nitrosoureas, becomes the site of a point mutation during DNA synthesis by preferentially base mispairing with thymine [65-71-4] rather than correctly base pairing with cytosine [71-30-7]. To repair this adduct, cells contain a limited amt. of O6-alkylguanine-DNA alkyltransferase (alkyltransferase) [92767-51-6], a protein which removes the alkyl group in a stoichiometric reaction. To prevent mutations, repair must occur before DNA replication takes place. Consequently, formation of point mutations is related inversely to the no. of alkyltransferase mols. and directly to the rate of DNA synthesis. Bone marrow hematopoietic precursors, the target for nitrosourea-induced leukemia, are deficient in alkyltransferase activity. Whether regenerating bone marrow is more susceptible to nitrosoureas than other organs due to persistently low levels of alkyltransferase activity during periods of increased cell proliferation and DNA synthesis was studied. Following syngeneic bone marrow transplantation, murine hematopoietic cells underwent rapid cell proliferation but alkyltransferase activity remained well below the activity in liver. After N-nitrosomethylurea [684-93-5] exposure, [3H]thymidine incorporation in rat bone marrow increased 3-fold and stem cell proliferation over 10-fold within 2 days of exposure, but alkyltransferase activity remained low. The relative susceptibility of bone marrow to mutagenic damage from O6-alkylguanine adducts was detd. by comparing the ratio of alkyltransferase activity to [3H]thymidine incorporation in marrow, kidney, and liver. In untreated animals, the ratio was lowest in bone marrow and decreased further 48 h after N-nitrosomethylurea exposure to only 21% that of kidney and 1% that of liver. Thus, proliferating hematopoietic precursors appear more likely to form point mutations following nitrosourea exposure than other rodent tissues because they undergo rapid proliferation soon after DNA damage and before O6-alkylguanine adducts can be repaired. The combination of rapid cell proliferation and low DNA repair capacity may be the mechanism of nitrosourea-induced leukemic transformation of the bone marrow.