Antitumor activities of newly synthesized 5-carbamoyl-1 H-imidazol-4yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4yl piperonylate.
In synthetic studies on the chemical modification of the nucleoside antibiotic bredinin, two new derivatives, 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4-yl piperonylate, were found to possess a potent antitumor activity in several experimental tumor systems, even though bredinin itself shows only in vitro cytotoxicity and thus lacks therapeutic effectiveness. These two derivatives of bredinin exhibited antitumor activity against a wide variety of tumors, including leukemias L1210 and P388, Lewis lung carcinoma, B16 melanoma, Colon 26 and 38 adenocarcinomas. Ehrlich carcinoma, and Sarcoma 180. It is noteworthy that these agents showed good therapeutic effects not only against ascitic types of tumors but also against a number of slow-growing solid tumor lines, particularly the ascitic and solid forms of Ehrlich carcinoma. At their optimal doses, both compounds effected a complete cure of all or most of the mice treated. Although the mechanisms of action of these compounds remain unknown, they are able to suppress in vivo tumor growth, presumably by being slowly anabolized in vivo to an active form and inhibiting purine de novo synthesis as bredinin does.
New AntitumorlmidazoleDerivative , 5-Carbamoyl-1 H-imidazol-4-yI Piperonylate , as an Inhibitorof PurineSynthesisand Its Activation by Adenine Phosphoribosyltransferas &
The mechanism of action of 5-carbamoyl-i H-imidazol-4-yI piperonylate (SL-i 250), which has a broad antitumor spec trum, was examined by in vitro cell culture and enzymatic studies. In the serum-containing culture medium, SL-1250 was rapidly deacylated to 4-carbamoylimidazolium 5-olate (SM i 08). Thus, SL-i 250 might be acting on the cells in the form of SM-i 08. The growth of L5i 78Y cells was completely in hibited by i o-@M SL-i 250. It should be noted that this growth inhibition was significantly reversed in the presence of equi molar concentrations of guanine, guanosine, or guanosine 5'monophosphate to those of SL-i 250. However, hypoxanthine and xanthine were not effective. These effects of purine addi tion were observed to be quite similar in growth inhibition by SM-i08. It was found that inosine 5'-monophosphate dehydrogenase (EC 1.2. 1.14; IMP dehydrogenase), a key enzyme of de novo purine synthesis, from Ehrlich carcinoma cells was inhibited by SM-i 08 only when 5-phospho-a-D-ribose 1-diphosphate (PRPP) and MgCI2 coexisted with SM-i 08. In contrast, a chem ically synthetic ribonucleotide of SM-i 08 inhibited IMP dehy drogenase without PRPPand MgCl2,and the mode of inhibition was competitive with the K value of 2 x i 0_8 M. On the other hand, the inhibition of either growth of L5i 78Y cells or IMP dehydrogenase in the presence of PRPP and MgCl2 by these compounds was reversed by adenine. A nu cleotide of SM-i 08 was chromatographically identified when [14C]SM-i 08 was incubated in the enzyme solution with PRPP and MgCl2. This conversion by enzyme was also inhibited by adenine. Viewed together, these results strongly suggest that SL i 250 is, after being converted to SM-i 08, activated to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7) and that this SM-i08 nucleotide blocks de novo syn thesis of guanosine 5'-monophosphate by inhibiting IMP de hydrogenase.
Drivers of Live Cattle Price in the Livestock Trading System of Central Cameroon
Livestock production and trade are critical for the food security and welfare of rural households in sub-Saharan Africa. In Cameroon, animal trade consists mainly of live cattle commercialized through livestock markets. Identifying the factors contributing to cattle price formation is critical for designing effective policies for sustainable production and for increasing food availability. In this study, we evaluated the influence of a range of individual- and market-level factors on the price of cattle that were sold in all transactions (n = 118,017) recorded over a 12-month period from 31 livestock markets in the main cattle production area of the country. An information-theoretic approach using a generalized additive mixed-effect model was implemented to select the best explanatory model as well as evaluate the robustness of the identified drivers and the predictive ability of the model. The age and gender of the cattle traded were consistently found to be important drivers of the price (p < 0.01). Also, strong, but complex, relationships were found between cattle prices and both local human and bovine population densities. Finally, the model highlighted a positive association between the number of incoming trading connections of a livestock market and the price of the traded live cattle (p < 0.01). Although our analysis did not account for factors informing on specific phenotypic traits nor breed characteristics of cattle traded, nearly 50% of the observed variation in live cattle prices was explained by the final model. Ultimately, our model gives a large scale overview of drivers of cattle price formation in Cameroon and to our knowledge is the first study of this scale in Central Africa. Our findings represent an important milestone in designing efficient and sustainable animal health management programme in Cameroon and ensure livelihood sustainability for rural households.