Synthesis of pyridine derivatives of L-phenylalanine as antisickling reagents.
Several bicyclic agents composed of L-phenylalanine coupled to various pyridines were synthesized: 2-, 3-, and 4-(L- phenylalanylamino )pyridine. All three compounds at 3 mM gave positive morphological antisickling effects on homozygous SS cells under reduced O2 tension. Studies on two of these compounds, 2- and 3-(L- phenylalanylamino )pyridine, showed that these agents increase the deoxy-HbS solubility ratio, Cs/ Cs0 , by 14% at 20 mM. Observed changes in the mean corpuscular hemoglobin concentration (MCHC) values of treated cells ranged from 4% at 1.3 mM to 15% at 5.6 mM in compound concentration. Very minor lytic activity was found for treated cells, indicating water uptake is responsible for changes in the MCHC. Further, exposure of sickle cells to a 3 mM concentration of these agents also increased by 6- to 7-fold cellular deformability of a treated erythrocyte population as compared to an untreated one at the same total O2 saturation of 47%. These agents demonstrate the potential of bicyclic compounds composed of a common constituent, L-Phe, in the development toward a viable therapeutic agent.
D000755:Anemia, Sickle Cell / Q000097:blood; D000986:Antisickling Agents / Q000138:chemical synthesis*; D004912:Erythrocytes / Q000187:drug effects; D006451:Hemoglobin, Sickle / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D012995:Solubility; D013329:Structure-Activity Relationship
D000986:Antisickling Agents; D006451:Hemoglobin, Sickle; D007202:Indicators and Reagents; C038875:deoxyhemoglobin, sickle