Simplified strigolactams as potent analogues of strigolactones for the seed germination induction of Orobanche cumana Wallr.

BACKGROUND: Strigolactones play an important role in the rhizosphere as signalling molecules stimulating the seed germination of parasitic weed seeds and hyphal branching of arbuscular micorrhiza, and also act as hormones in plant roots and shoots. Strigolactone derivatives, e.g. strigolactams, could be used as suicidal germination inducers in the absence of a host crop for the decontamination of land infested with parasitic weed seeds. RESULTS: We report the stereoselective synthesis of novel strigolactams, together with some of their critical physicochemical properties, such as water solubility, hydrolytic stability, as well as their short soil persistence. In addition, we show that such strigolactams are potent germination stimulants of O. cumana parasitic weed seeds and do not affect the seed germination and the root growth of sunflower. CONCLUSIONS: The novel strigolactam derivatives described here compare favourably with the corresponding GR-28 strigolactones in terms of biological activity and physicochemical properties. However, we believe strigolactone and strigolactam derivatives require further structural optimisation to improve their soil persistence to demonstrate a potential for agronomical applications. © 2016 Society of Chemical Industry.

Synthesis and stability of boratriazaroles.

We describe the synthesis and stability analysis of novel boratriazaroles that can be viewed as bioisosteres of imidazoles or pyrazoles. These heterocycles could conveniently be obtained by condensing a boronic acid and amidrazone 1 in various solvents. A detailed stability analysis of selected compounds at different pH values as a function of time led to the identification of steric hindrance around the boron atom as a key element for stabilization.

Chemicals inducing seed germination and early seedling development.

Seed germination and early seedling development are essential events in the plant life cycle that are controlled largely by the interplay and cross-talk between several plant hormones. Recently, major progress has been achieved in the elucidation at the molecular level of the signalling of these phytohormones. In this review, we summarise the data for the most promising classes of compounds, which could find potential agronomic applications for promoting seed germination and early seedling development even under abiotic stress conditions. Structural modifications of plant hormones are required to improve their biological performance and their specificity to allow commercial application.

Molecular mechanism of action of microtubule-stabilizing anticancer agents.

Microtubule-stabilizing agents (MSAs) are efficacious chemotherapeutic drugs widely used for the treatment of cancer. Despite the importance of MSAs for medical applications and basic research, their molecular mechanisms of action on tubulin and microtubules remain elusive. We determined high-resolution crystal structures of αß-tubulin in complex with two unrelated MSAs, zampanolide and epothilone A. Both compounds were bound to the taxane pocket of ß-tubulin and used their respective side chains to induce structuring of the M-loop into a short helix. Because the M-loop establishes lateral tubulin contacts in microtubules, these findings explain how taxane-site MSAs promote microtubule assembly and stability. Further, our results offer fundamental structural insights into the control mechanisms of microtubule dynamics.

Total synthesis of (-)-zampanolide and structure-activity relationship studies on (-)-dactylolide derivatives.

A new total synthesis of the marine macrolide (-)-zampanolide (1) and the structurally and stereochemically related non-natural levorotatory enantiomer of (+)-dactylolide (2), that is, ent-2, has been developed. The synthesis features a high-yielding, selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction to close the 20-membered macrolactone ring of 1 and ent-2. The ß-keto phosphonate/aldehyde precursor for the ring-closure reaction was obtained by esterification of a ω-diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent-2. THP ring formation was accomplished through a segment coupling Prins-type cyclization. Employing the same overall strategy, 13-desmethylene-ent-2 as well as the monocyclic desTHP derivatives of 1 and ent-2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC(50) values, while ent-2, which lacks the diene-containing hemiaminal-linked side chain of 1, is 25- to 260-fold less active. 13-Desmethylene-ent-2 as well as the reduced versions of ent-2 and 13-desmethylene-ent-2 all showed similar cellular activity as ent-2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1. Oxidation of the aldehyde functionality of ent-2 gave a carboxylic acid that was converted into the corresponding N-hexyl amide. The latter showed only µM antiproliferative activity, thus being several hundred-fold less potent than 1.

Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,ß-heterodimers and microtubules.

Zampanolide and its less active analog dactylolide compete with paclitaxel for binding to microtubules and represent a new class of microtubule-stabilizing agent (MSA). Mass spectrometry demonstrated that the mechanism of action of both compounds involved covalent binding to ß-tubulin at residues N228 and H229 in the taxane site of the microtubule. Alkylation of N228 and H229 was also detected in α,ß-tubulin dimers. However, unlike cyclostreptin, the other known MSA that alkylates ß-tubulin, zampanolide was a strong MSA. Modeling the structure of the adducts, using the NMR-derived dactylolide conformation, indicated that the stabilizing activity of zampanolide is likely due to interactions with the M-loop. Our results strongly support the existence of the luminal taxane site of microtubules in tubulin dimers and suggest that microtubule nucleation induction by MSAs may proceed through an allosteric mechanism.

Synthesis of (-)-dactylolide and 13-desmethylene-(-)-dactylolide and their effects on tubulin.

An efficient new synthesis has been elaborated for non-natural (-)-dactylolide ((-)-2) and its 13-desmethylene analogue 4, employing a HWE-based macrocyclization approach with beta-keto-phosphonate/aldehyde 19 and the respective 13-desmethylene derivative as the key intermediates. Both (-)-2 and 4 as well as the corresponding C20 alcohols inhibit human cancer cell proliferation with IC(50) values in the sub-micromolar range and induce the polymerization of tubulin in vitro.