Design of potent ABA receptor antagonists based on a conformational restriction approach

• Published in: Organic & biomolecular chemistry 2020-07, Vol.18 (26), p.4988-4996
• Main Authors: Takeuchi, Jun, Nagamiya, Hikaru, Moroi, Sayaka, Ohnishi, Toshiyuki, Todoroki, Yasushi
• Format: Article
• Language: English
• Subjects: Abscisic acid; Affinity; Arabidopsis; Chains; Chemical compounds; Germination; Molecular conformation; NMR; Nuclear magnetic resonance; Plant hormones; Receptors; Regulatory mechanisms (biology); Seed germination; Signaling
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d0ob01017k

The physiological functions of the plant hormone abscisic acid (ABA) are triggered by interactions between PYR/PYL/RCAR receptors (PYLs) and group-A protein phosphatases 2C (PP2Cs). PYL agonists/antagonists capable of inducing/disrupting these interactions would be valuable in investigating the regulatory mechanisms of ABA signaling. Previously, we developed (+)-PAO4, a high-affinity PYL antagonist, by conformationally restricting the S -hexyl chain of our first reported PYL antagonist, 3′-hexylsulfanyl-ABA. Although (+)-PAO4 shows a greater binding affinity for Arabidopsis PYL5 compared with 3′-hexylsulfanyl-ABA, it is not able to completely block the ABA responses both in vitro and in vivo . Therefore, we designed novel conformationally restricted PYL antagonists in which the O -butyl chain of (+)-PAO4 was replaced with a pentyl (PAC4), a pentyne (PAT3) or a pentadiyne (PATT1) chain. (+)-PAT3 and (+)-PATT1 suppressed the ABA-induced inhibition of Arabidopsis seed germination more strongly than (+)-PAO4, but contrary to expectations, the affinity of each compound for PYL5 was almost the same as that of (+)-PAO4. Subsequent biochemical analyses revealed that unlike (+)-PAO4, (+)-PAT3 and (+)-PATT1 completely abolished ABA-induced PYL-PP2C interactions without partial agonistic activities. The superior PYL antagonist functions of (+)-PAT3 and (+)-PATT1 over (+)-PAO4 may explain their potent antagonistic activities against exogenous ABA in vivo . Furthermore, (+)-PAT3 and (+)-PATT1 also suppressed ABA responses in rice, indicating that both compounds are useful chemical tools for ABA-signaling studies, not only in dicots but also in monocots. Conformationally restricted analogs of (+)-PAO4, an abscisic acid receptor antagonist, were synthesized to improve its potency.