Synthesis And Biological Evaluation Of Novel Abscisic Acid Analogs

Abscisic acid(ABA,1)is a key phytohormone that plays a central role in coordinating the physiological processes of plants.Furthermore,ABA can conduct the plant to respond quickly to environmental stresses such as drought by inducing stomata closure and activating the expression of stress-resistant genes.Therefore.ABA is highly valued as an “inducer of stress resistance',.The agricultural uses of ABA as a plant growth regulator have been investigated,but its cost,ready isomerization to the biologically inactive 2E-isomer by light and rapid conversion to inactive oxidative metabolites make wide use impractical.Researchers had been successfully synthesized a variety of highly active anti-metabolites ABA analogs,some of which compounds active on seed germination and resilience even better than ABA.However,all of these studies remained at the experimental stage.So far there is no ABA analogs application to agricultural production.Therefore,it is very necessary to develop novel structurally stable ABA analogs both to metabolic enzyme and light and approach these compounds in simple and inexpensive pathways.In this paper,based on preliminary work,we synthesized several types of ABA analogs which their biological activities has been systematically studied and achieved important results are as follows:1.Based on previous work of our group,the cis-2,3-cyclipropanated ABA(cis-2,3-CpABA)were synthesized via optimized Simmons-Smith cyclopropanation and BINOL resolution,thus 95a and 95b were given as their racemic fonns.They were chirally resolved by preparative HPLC using a column with a chiral ligand to yield all four steric isomers of cis-2,3-CpABA.The bioassay results indicated that configuration of Cl' was the most important factor for activity,but the configuration of the cyclopropyl was minor factor.2.We had developed a novel regioselective addition of acetyl ides to enediones that affords the corresponding l-ethynylcydohex-2-enol derivatives with excellent regioselectivity and high yield.This synthetic strategy was applied to the manufacture of iso-ABA 145.The racemic acid was resolved by preparative HPLC,yielded the respective enantiopure isomers.The simplified synthetic pathway of eliminating the protection and deprotection improved synthetic efficiency and was more suitable for larger scale prepararion.The bioassays experimental results showed(+)-145 exhibited high ABA-like activity,including the ability to effectively inhibit seed germination and seedling growth.The analogs146,147,148 were also prepared and biological activities were investigated.3.The 2',3'-benzoABA(PhABA)analogs 58,164,165 and 167 were synthesized via oxidation of the benzylic methylene and selective protecting carbonyl group.The iso-2',3'-benzoABA(iso-2'.3'-PhABA)analogs 169 and 170 were synthesized via regioselective addition of acetyl ides to enediones.The racemic acid 169 was resolved by preparative chiral HPLC.There was a great effect on activity after methoxy substituented.(+)-iso-PhABA(+)-169 inhibited the germination of lettuce seed and Arabidopsis seed ten and two times more strongly than(+)-ABA.4.Most of the(+)-iso-PhABA-bound PYLs inhibited about 50% to 80% activity of the phosphatase HABl,and the effect of(+)-169 was stronger than(-)-169 generally.We successfully obtained and determined the complex structures of PYLIO with these two 169 stereoisomers.The ligands were arranged in the PYLs ligand-binding pocket through hydrogen bond and van dev Waals interactions.(+)-169 made more hydrophobic interactions with the residues of the binding pocket in PYUO,and most of these residues were highly conserved in all 14 PYLs proteins,so most PYLs bound tighter to(+)-169 than to(-)-169.Generally,our structural analyses support the notion that the hydrophobic residues at the entrance to the ligand-binding pocket form a network to close the gate loop,and the strong steric constraints in the binding pocket also affect the selectivity of(+)/(-)-169 in PYLs.The(+)-169 is a good selective agonist for PYLs.They can be a good start for drug design.5.The indanone ABA analogs were synthesized and bioassays experimental results showed six-membered ring was the key structural units for activity.In summary,we had synthesized 19 ABA analogs,bioassay results showed that some products with industrial production potential.This study supplied a novel strategy on designing ABA analogues,and provided a new way to accelerate the application of ABA-like phytohormones in agriculture.