Design,Synthesis And Preliminary Anti-radiation Activity Of Novel LPAR2 Agonists

Radiation usually refers to ionizing radiation in life.Ionizing radiation possesses high enough energy to cause ionization of matter,including high-energy electromagnetic wave as X-rays,?rays and several kinds of common particle radiation such as?particles,?particles and so on.Ionizing radiation directly acts on radiation-sensitive biological macromolecules such as nucleic acids,proteins,or stimulates the body to generate excess free radicals indirectly damaging the living body to induce damage to the cells,tissues,organs and the whole body of life.Anti-radiation drug refers to drugs that are applied before or after radiation exposure to reduce systemic or local radiation damage and to aid in the treatment and recovery,they are mainly divided into natural and non-natural sources of anti-radiation drugs.Due to the complexity and variety of mechanisms that cause radiation damage,the variety of programs and drugs for treating radiation injuries.However,the existing anti-radiation drugs are only effective for mild and moderate acute radiation syndromes,lack effective drugs for moderate and severe acute radiation syndromes.In addition,the existing drugs also have serious toxic and side effects,so it is the main direction of our research to look for high-efficiency and low-toxic new radiation protection and therapeutic agents.The repair of radiation damage is related to a variety of receptor signals,where the LPAR2 signal is involved in cell survival,proliferation,and differentiation.In this study,we selected DBIBB that is a specific LPAR2 agonist as the lead compound to carry out a series of structural optimization and transformation,expecting to obtain LPAR2 agonists with better or equivalent activity and better clinical application effect.The target compound is designed to retain the 1,8-naphthalimide of the tail group or to be replaced by?E-?-4-?prop-1-en-1-yl?phenol;the linker remains hydrophobic tetralic chain or with a hydrophobic aromatic ring;the linking group retains the sulfamoyl group or is replaced by an amide group;the head retains the aromatic acid or introduces a halogen element in the meta-position of the carboxylic acid or the head aromatic acid is replaced by a chain carboxylic acid.During the synthesis of the target compounds,I₁,I₇ and II₁,II₇ were obtained with 1,8-naphthalimide and?E?-4-?prop-1-en-1-yl?phenol as raw materials via two-step nucleophilic substitution and hydrolysis.Compounds I₂^I₆,II₆,I₈^I₁₂,II₈^II₁₂ were obtained by acyl chloride chlorination,two-step nucleophilic substitution reactions and hydrolysis with 5-chlorovaleric acid and 4-chloromethyl benzoic acid as the starting material respectively;The target compound II₂^II₅ was obtained by using trans-anethole as a starting material through demethylation,nucleophilic substitution,hydrolysis,acid chlorination,nucleophilic substitution and hydrolysis.The structure of the target compound was confirmed by ¹H NMR and MS.In this experiment,23 target compounds of I₂^I₁₂ and II₁^II₁₂ have been successfully designed and synthesized and the structures of these compounds have not been reported in the literature.The anti-radiation activity of the target compounds was tested by in vitro anti-radiation experiments of human umbilical vein endothelial cells?HUVEC?.The results showed that the compounds I₅,I₆ and II₁ had good anti-radiation activity,which provided the experimental basis for the structural transformation of the latter compounds.