Design and chemical synthesis of root gravitropism inhibitors: Bridged analogues of ku-76 have more potent activity

Previously, we found (2Z,4E)-5-phenylpenta-2,4-dienoic acid (ku-76) to be a selective inhibitor of root gravitropic bending of lettuce radicles at 5 μM, with no concomitant growth inhibition, and revealed the structure–activity relationship in this inhibitory activity. The conformation of ku-76 is flexible owing to the open-chain structure of pentan-2,4-dienoic acid with freely rotating single bonds, and the (2Z)-alkene moiety may be isomerized by external factors. To develop more potent inhibitors and obtain insight into the target biomolecules, various analogues of ku-76, fixed through conformation and/or configuration, were synthesized and evaluated. Stereochemical fixation was effective in improving the potency of gravitropic bending inhibition. Finally, we found highly potent conformational and/or configurational analogues (ku-257, ku-294 and ku-308), that did not inhibit root growth. The inhibition of root curvature by these analogues was comparable to that of naptalam.