The acid-catalyzed synthesis of substituted 3,4-dihydro-2(l//)-pyrimidinones from a variety of precursors was studied. The major products of the condensation of 3-methoxyacrylate with urea and monomethylurea are 5-carbomethoxy-4-carboxymethyl-3,4-dihydro-2(l//)-pyrimidinone and its N-l methyl derivative. The decarboxylated derivatives, 5-carbomethoxy-4-methyl-3,4-dihydro-2(l//)-pyrimidinone and 5-carbomethoxy-l ,4dimethyl-3,4-dihydro-2( 1 //j-pyrimidinone, are minor products of the same reaction. syw-Dimethylurea produces 5-carbomethoxy-3,4-dihydro-l,3,4-trimethyl-2(l//)-pyrimidinone and 1,3-dimethyluracil, both in small yield. An integrated mechanism for these reactions is proposed involving a preliminary acid-catalyzed aldol condensation and subsequent reactions of a carbonium ion formed from the aldol intermediate. An interaction, probably through hydrogen bonding, is shown to occur between the carboxylic group on the substituent at C-4 and the N-3 group in 5-carbomethoxy-4-carboxymethyl-3,4-dihydro-2(l//)-pyrimidinone. Its effect upon the hydrolysis of an ester of the same carboxylic group has been demonstrated. The reaction of methyl 2-dimethoxymethyl-3-methoxypropionate with ureas also produces 5-carbomethoxy-3,4-dihydro-2(l//)-pyrimidinones. Factors influencing the orientation of these condensations are considered. It is concluded that the more nucleophilic of the two nitrogens in a substituted urea reacts first by displacing the protonated alkoxy group, which is activated through an enol-allyl system derived from the aldehyde function. Cyclization to the 3,4-dihydro-2(l//)-pyrimidinone is completed by reaction of the free ureide nitrogen with the aldehyde group. The results of the condensations of 2-dimethoxymethyl-3-methoxy-l-propanol and 2-hydroxymethyl-1,1,3,3-tetramethoxypropane with ureas are consistent with the proposed enhanced reactivity of an allylic center as compared to an aldehyde function and with the corollary carbonium ion mechanism. This mechanism also applies to the Biginelli pyrimidine synthesis in which the limiting step is now considered to be an in situ aldol condensation required to produce the reactive unit which condenses with a urea to give the corresponding 3,4-dihydro-2(l//)-pyrimidinone. The mechanism proposed here for the Biginelli synthesis explains the course of reactions which had previously been considered "anomalous."

The growth of human cancer cells from lung, breast, and uterine tumors was selectively inhibited in a dose-dependent manner by ozone at 0.3 to 0.8 part per million of ozone in ambient air during 8 days of culture. Human lung diploid fibroblasts served as noncancerous control cells. The presence of ozone at 0.3 to 0.5 part per million inhibited cancer cell growth 40 and 60 percent, respectively. The noncancerous lung cells were unaffected at these levels. Exposure to ozone at 0.8 part per million inhibited cancer cell growth more than 90 percent and control cell growth less than 50 percent. Evidently, the mechanisms for defense against ozone damage are impaired in human cancer cells.

The relationship between 3a and 20/3 activity in 3a,20/3-hydroxysteroid dehydrogenase (3a,20/3-HSD; EC 1.1.1.53) from Streptomyces hydrogenans was studied by affinity alkylation with 17-(bromoacetoxy)progesterone (17-BAP) and 5a-dihydrotestosterone 17-bromoacetate (DTB). Both 17-BAP and DTB are substrates for 3a,20/3-HSD and must therefore bind at the enzyme active site. 17-BAP and DTB irreversibly and simultaneously inactivate the 3 a and 20/3 activity of 3a,20/3-FISD at pH 7.0 and 25 °C, in a time-dependent manner, producing first-order kinetic half-times of 25 and 67 h, respectively. Biphasic kinetics from inactivation

No abstract

No abstract