The novel herbicide icafolin-methyl is a plant-specific inhibitor of tubulin polymerization.

BACKGROUND: Without controlling weeds, it is estimated that about one third of global crop yields would be lost. Herbicides remain the most effective solution for weed control, but they face multiple challenges, such as the emergence and growth of resistant weed populations. Consequently, there is an urgent need for either herbicides with new modes of action or at least novel chemistries within established modes of action, with outstanding efficacy but without showing cross-resistance to the herbicides present in the prospective markets. RESULTS: Icafolin-methyl is a novel herbicide with a unique biological profile. It is hydrolyzed in planta to the carboxylic acid icafolin. After post-emergence application icafolin-methyl and icafolin both show high efficacy against the most relevant competitive weeds in cold and warm season cropping systems at low application rates, including resistant black-grass and rye-grass biotypes. Biochemical and genetic evidence is provided that icafolin-methyl and icafolin inhibit plant tubulin polymerization probably by binding to ß-tubulins. CONCLUSION: Icafolin-methyl is a novel non-selective herbicide with an established mode of action, but with a superior potency and spectrum, specifically after foliar application. This makes icafolin-methyl fundamentally different from existing tubulin polymerization inhibiting herbicides. It complements the farmers weed control toolbox, particularly with respect to resistance management. © 2024 Society of Chemical Industry.

Scaffold hopping approaches for the exploration of herbicidally active compounds inhibiting Acyl-ACP Thioesterase.

BACKGROUND: The sustainable control of weed populations is a significant challenge facing farmers around the world. Although various methods for the control of weeds exist, the use of small molecule herbicides remains the most effective and versatile approach. Striving to find novel herbicides that combat resistant weeds via the targeting of plant specific modes of action (MoAs), we further investigated the bicyclic class of acyl-acyl carrier protein (ACP) thioesterase (FAT) inhibitors in an effort to find safe and efficacious lead candidates. RESULTS: Utilizing scaffold hopping and bioisosteric replacements strategies, we explored new bicyclic inhibitors of FAT. Amongst the investigated compounds we identified new structural motifs that showed promising target affinity coupled with good in vivo efficacy against commercially important weed species. We further studied the structure-activity relationship (SAR) of the novel dihydropyranopyridine structural class which showed promise as a new type of FAT inhibiting herbicides. CONCLUSION: The current work presents how scaffold hopping approaches can be implemented to successfully find novel and efficacious herbicidal structures that can be further optimized for potential use in sustainable agricultural practices. The identified dihydropyranopyridine bicyclic class of herbicides were demonstrated to have in vitro inhibitory activity against the plant specific MoA FAT as well as showing promising control of a variety of weed species, particularly grass weeds in greenhouse trials on levels competitive with commercial standards. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis.

The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure-activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient's quality of life.

Synthesis and biological evaluation of two agents for imaging estrogen receptor ß by positron emission tomography: challenges in PET imaging of a low abundance target.

INTRODUCTION: Independent measurement of the levels of both the estrogen receptors, ERα and ERß, in breast cancer could improve prediction of benefit from endocrine therapies. While ERα levels can be measured by positron emission tomography (PET) using 16α-[(18)F]fluoroestradiol (FES), no effective agent for imaging ERß by PET has yet been reported. METHODS: We have prepared the fluorine-18 labeled form of 8ß-(2-fluoroethyl)estradiol (8BFEE(2)), an analog of an ERß-selective steroidal estrogen, 8ß-vinylestradiol; efficient incorporation of fluorine-18 was achieved, but required very vigorous conditions. We have examined the biodistribution of this compound, as well as of Br-041, an analog of a known non-steroidal ERß-selective ligand (ERB-041), labeled with bromine-76. Studies were done in immature female rodents, with various pharmacological and endocrine perturbations to assess ERß selectivity of uptake. RESULTS: Little evidence of ERß-mediated uptake was observed with either [(18)F]8BFEE(2) or [(76)Br]Br-041. Attempts to increase the ERß content of target tissues were not effective and failed to improve biodistribution selectivity. CONCLUSIONS: Because on an absolute basis level, ERß levels are low in all target tissues, these studies have highlighted the need to develop improved in vivo models for evaluating ERß-selective radiopharmaceuticals for use in PET imaging. Genetically engineered breast cancer cells that are being developed to express either ERα or ERß in a regulated manner, grown as xenografts in immune-compromised mice, could prove useful for future studies to develop ER subtype-selective radiopharmaceuticals.

Structure-based design, synthesis and in vitro characterization of potent 17beta-hydroxysteroid dehydrogenase type 1 inhibitors based on 2-substitutions of estrone and D-homo-estrone.

In search for specific drugs against steroid-dependent cancers we have developed a novel set of potent inhibitors of steroidogenic human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD 1). The X-ray structure of 17beta-HSD 1 in complex with estradiol served as basis for the design of the inhibitors. 2-Substituted estrone and D-homo-estrone derivatives were synthesized and tested for 17beta-HSD 1 inhibition. The best 17beta-HSD 1 inhibitor, 2-phenethyl-D-homo-estrone, revealed an IC(50) of 15 nM in vitro. The inhibitory potency of compounds is comparable or better to that of previously described inhibitors. An interaction within the cofactor binding site is not necessary to obtain this high binding affinity for substances developed.

Dissecting physiological roles of estrogen receptor alpha and beta with potent selective ligands from structure-based design.

The distinct roles of the two estrogen receptor (ER) isotypes, ERalpha and ERbeta, in mediating the physiological responses to estrogens are not completely understood. Although knockout animal experiments have been aiding to gain insight into estrogen signaling, additional information on the function of ERalpha and ERbeta will be provided by the application of isotype-selective ER agonists. Based on the crystal structure of the ERalpha ligand binding domain and a homology model of the ERbeta-ligand binding domain, we have designed steroidal ligands that exploit the differences in size and flexibility of the two ligand binding cavities. Compounds predicted to bind preferentially to either ERalpha or ERbeta were synthesized and tested in vitro using radio-ligand competition and transactivation assays. This approach directly led to highly ER isotype-selective (approximately 200-fold) and potent ligands. To unravel physiological roles of the two receptors, in vivo experiments with rats were conducted using the ERalpha- and ERbeta-selective agonists in comparison to 17beta-estradiol. The ERalpha agonist induced uterine growth, caused bone-protective effects, reduced LH and FSH plasma levels, and increased angiotensin I, whereas the ERbeta agonist did not at all or only at high doses lead to such effects, despite high plasma levels. It can thus be concluded that estrogen effects on the uterus, pituitary, bone, and liver are primarily mediated via ERalpha. Simultaneous administration of the ERalpha and ERbeta ligand did not lead to an attenuation of ERalpha-mediated effects on the uterus, pituitary, and liver parameters.

Impact of isotype-selective estrogen receptor agonists on ovarian function.

Other isotype-selective estrogen receptor (ER) agonists, the selective ERalpha agonist 3,17-dihydroxy-19-nor-17alpha-pregna-1,3,5 (10)-triene-21,16alpha-lactone and the selective ERbeta agonist 8-vinylestra-1,3,5 (10)-triene-3,17beta-diol, were used in hypophysectomized rats, gonadotropin-releasing hormone antagonist-treated mice, as well as intact rats to elucidate the effects of isotype-selective estrogens on the physiology of folliculogenesis and ovulation. In hypophysectomized rats and gonadotropin-releasing hormone antagonist-treated mice, the ERbeta agonist caused stimulation of early folliculogenesis, a decrease in follicular atresia, induction of ovarian gene expression, and stimulation of late follicular growth, accompanied by an increase in the number of ovulated oocytes similar to 17beta-estradiol (E2). In contrast, the ERalpha agonist had little or no effect on these parameters, implying that direct estrogen effects on ovarian follicular development are mediated by ERbeta. In intact rats, E2 and the ERalpha agonist dose-dependently inhibited ovulation, in contrast to the ERbeta agonist. On the other hand, the ERbeta agonist did not stimulate uterine weight in intact rats, in contrast to E2 and the ERalpha agonist. This finding is in line with the assumption that estrogen mediated ovulation inhibition and stimulation of uterine growth are mediated by ERalpha but not by ERbeta