Design, syntheses, and conformational study of angiogenesis inhibitors

Since anti-angiogenesis could lead to the suppression of tumor growth, angi ogenesis inhibitors have received particular attention for their therapeuti c potential. In this study, two angiogenic inhibitors using the bioactive s equence from the kringle 5, AK1(KLYDY), AK2(KLWDF) were designed and synthe sized. We have investigated their solution structures using NMR spectroscop y and their activities as angiogenesis inhibitors. AK2 has, an intramolecul ar hydrogen bon d between the side chain amino proton of Lys I and the carb oxyl oxygen of Asp4 with a N . . .O distance of 3.27 Angstrom, while AK1 sh ows more flexible structures than AK2. Indole ring in, Trp is much bigger t han the phenyl ring in Tyr and may have good face-to-edge interaction enfor cing more rigid and constrained conformational features of AK2. Because of this relatively stable structure, Trp3 in AK2 may have better hydrophobic i nteraction with Phe5 than Tyr3 in AK1 if two adjacent aromatic groups are l ocated in hydrophobic pocket of receptor. Since AK2 shows the similar anti- angiogenic activities to AK1, we are also, able to confirm that the activit y of AK1 is irrelevant to the Tyr phosphorylation. More rigid drug with hig her activities can be provided by the mimetic approaches. For the further d evelopment of the angiogenesis inhibitors, these conformational studies on our lead peptides will be helpful in design of peptidomimetics.