Potent Analogues of Abscisic Acid – Identifying Cyano‐Cyclopropyl Moieties as Promising Replacements for the Cyclohexenone Headgroup

Abstract

Synthetic analogues of plant hormone abscisic acid (ABA) bearing a yet unexplored head group motif were prepared based on a combination of agrochemical experience, in vivo hits and structure‐based design. It could thus be explored how modifying key parts of ABA's cyclohexenone unit influenced receptor affinity and in vivo efficacy against drought stress in selected crops. Cyano‐cyclopropyl groups proved to be suitable replacements of the cyclohexanone moiety leading to ABA analogues with strong activity in vitro and in vivo. Their efficient and versatile synthesis proceeded via Stille or Sonogashira couplings as the key steps. Combining novel cyano‐cyclopropyl headgroups with previously identified substituents in the terpenoid side chain afforded the most promising effects against drought stress in crops, particularly canola and wheat.

Abscisic Acid Receptors and Coreceptors Modulate Plant Water Use Efficiency and Water Productivity

“…The improvement of iWUE in C 3 crops such as wheat could be achieved either by genetic means or by using ABA agonists selective for distinct ABA receptors. Some ABA agonists have been identified with preferential binding to distinct ABA receptors (Benson et al, 2015;Helander et al, 2016;Vaidya et al, 2017;Frackenpohl et al, 2018aFrackenpohl et al, , 2018b. Engineering of ABA receptors for novel ligands offers another approach to activate a unique ABA receptor (Park et al, 2015) or the modulated expression of ABA receptor components as shown for Arabidopsis.…”

“…More recently, application of ABA and ABA agonists (Okamoto et al, 2013;Park et al, 2015;Cao et al, 2017), ectopic expression of ABA receptors (Santiago et al, 2009;Mosquna et al, 2011;Pizzio et al, 2013;González-Guzmán et al, 2014;Yang et al, 2016;Zhao et al, 2016), and reduced expression of ABA coreceptors (Rubio et al, 2009;Antoni et al, 2012) have been shown to minimize plant transpiration, and in several cases to boost survival rates under severe water deficit. A plethora of ABA agonists (Wilen et al, 1993;Benson et al, 2015;Vaidya et al, 2017;Frackenpohl et al, 2018aFrackenpohl et al, , 2018bNemoto et al, 2018) and antagonists (Takeuchi et al, 2014;Ito et al, 2015;Rajagopalan et al, 2016;Ye et al, 2017) were developed that allow the modulation of ABA responses.…”

Synthesis and Exploration of Abscisic Acid Receptor Agonists Against Dought Stress by Adding Constraint to a Tetrahydroquinoline‐Based Lead Structure

“…Further experimental details have been described in the suppl. material, as well as in references, [31,32] and. [42] Ethyl 3-{2-[1,1'-bi(cyclopropyl)-2-ylamino]-5-nitrophenyl}propanoate (650 mg, 2.04 mmol) was dissolved in abs.…”

“…Recently, we have shown that cyano-cyclopropyl groups in ABA analogues 2 a-c served as isosteres of the cyclohexanone moiety giving rise to compounds with strong activity in vitro and in vivo. [22] Synthetic agonists of RCAR/(PYR/PYL) receptor proteins have also been prepared by other groups, [23][24][25] and the independent studies have afforded three different generations of sulfonamide lead structures. Likewise, naphthyl sulfonamides, such as 1 st generation lead structure pyrabactin 3 a, [26,27] structurally related pyrimidine 3 b, as well as five-membered analogs 4 a-b, [28] have all exhibited good initial receptor affinity, albeit paired with moderate beneficial effects in in vivo tests (Figure 1).…”

Chemical activation of Arabidopsis SnRK2.6 by pladienolide B

“…5 However, because ABA itself induces negative effects on growth and is degraded quickly, ABA derivatives have been studied intensively. [6][7][8] Alternatively, a chemical that activates specific parts of the ABA signaling could be used for improving crop stress tolerance and for studying physiological mechanisms of stress responses.…”