Sixty-five derivatives and analogs of the antitumor agent, mycophenolic acid (1), have been obtained by modifying all positions of the molecule except C-V. None of these compounds was as effective as 1 in suppressing cell division in mouse fibroblasts cultured in vitro. The most active analog (56), in which the MeO of 1 was replaced by EtO, had about 12% of the activity of 1. Although 0-acetate 51, alcohol 20, and aldehyde 30 were equiactive with 1 against transplanted tumors in rodents, presumably because of in vivo conversion into 1, no compound having a greater antitumor effect than that of 1 was obtained.Mycophenolic acid (1), a mold metabolite first isolated in 1896,1 has been shown by several groups2 3to have antitumor properties and the compound is presently undergoing clinical trial. Structure 1 was proposed in 1952s and confirmed in 1957.4 A recent total synthesis5 has confirmed the trans configuration at the double bond.5 1 The present paper reports derivatives and analogs of 1 which were prepared to determine the structural features necessary for antitumor activity.Chemistry.-It was established early that a variety of simple substituted phenols including 7-hydroxyphthalan-l-one and 6-allyl-7~hydroxyphthalan-l-one (2) were devoid of antitumor properties. Compound 5, prepared from 3 by the sequence (a) oxidation with 0s04-NaI04 to give 4, (b) condensation of 4 with Ph3P=C-(Me)CO»Et; and (c) hydrolysis of the resulting ester with MeSO3H-90% HCOTI,6 was also devoid of antitumor properties indicating that most of the structural features of 1 were probably required for biological activity. Accordingly each of the substituents of 1 was modified in turn as described below.Attempted O-acetylation of 5, as a preliminary to further modification of the C-6 substituent unex-
A method of preparing viable cells from dog gastric mucosa is described. Cyclic AMP in these cells is elevated by histamine and 4-methyl histamine but 2-methyl histamine is only a weak agonist. The effects on cyclic AMP levels are inhibited competitively by metiamide and burimamide which give apparent KBvalues of 3.5x10-7 M and 2.3x10-6 M, respectively. These values are similar to those reported for other histamine H2-receptor systems. The H1-receptor antagonists, mepyramine and chlorpheniramine, have no inhibitory effect on the histamine induced elevation of cyclic AMP: promethazine inhibits the system but not by a competitive mechanism. It is concluded that the histamine stimulated adenylate cyclase system is probably located in the parietal cell component.
This special report was developed to communicate policy and procedures for free-standing acute inpatient rehabilitation hospitals (AIRHs) to protect patients and healthcare personnel and to prevent further spread of severe acute respiratory syndrome coronavirus 2. The recommended policies were developed in conjunction with the New Mexico Department of Health and hospital leadership. As we attain additional knowledge and experience during this pandemic, suggestions of best practice will continue to evolve for AIRHs. The authors encourage readers to work with local regulatory officials to ensure regulatory compliance as well as respect of the availability of local resources.
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