Synthesis and evaluation of small molecule inhibitors of LSD1 for use against MYCN-expressing neuroblastoma.

The epigenetic regulator lysine specific demethylase 1 (LSD1), a MYCN cofactor, cooperatively silences MYCN suppressor genes. Furthermore, LSD1 has been correlated with adverse effects in neuroblastic tumors by propagating an undifferentiated, malignant phenotype. We observed that high LSD1 mRNA expression in MYCN-expressing neuroblastoma (NB) correlated with poor prognosis, implicating LSD1 as an oncogenic accomplice in high-grade NB. Thus, LSD1 inhibition is a potential strategy for targeting treatment-resistant MYCN-expressing NB. Tranylcypromine-based covalent LSD1 inhibitors have demonstrated anti-tumor activity but are associated with undesirable off-target effects, such that only 2 non-covalent LSD1 inhibitors are in clinical trials. We now report 3 novel scaffolds for reversible LSD1 inhibition: 2-(arylsulfonamido)benzoic acid, N-(2-(1H-tetrazol-5-yl)phenyl)benzenesulfonamide and 2-(arylcarboxamido)benzoic acid analogues. The most active of these analogues, compound 48, exhibited potent and selective mixed reversible inhibition of LSD1 (IC50 = 0.58 µM) and significantly increased global H3K4me2 in NB cells. In addition, combination treatment with 48 and bortezomib in NB cells results in a synergistic effect.

New Transmission-Selective Antimalarial Agents through Hit-to-Lead Optimization of 2-([1,1'-Biphenyl]-4-carboxamido)benzoic Acid Derivatives.

Malaria elimination requires multipronged approaches, including the application of antimalarial drugs able to block human-to-mosquito transmission of malaria parasites. The transmissible gametocytes of Plasmodium falciparum seem to be highly sensitive towards epidrugs, particularly those targeting demethylation of histone post-translational marks. Here, we report exploration of compounds from a chemical library generated during hit-to-lead optimization of inhibitors of the human histone lysine demethylase, KDM4B. Derivatives of 2-([1,1'-biphenyl]-4-carboxamido) benzoic acid, around either the amide or a sulfonamide linker backbone (2-(arylcarboxamido)benzoic acid, 2-carboxamide (arylsulfonamido)benzoic acid and N-(2-(1H-tetrazol-5-yl)phenyl)-arylcarboxamide), showed potent activity towards late-stage gametocytes (stage IV/V) of P. falciparum, with the most potent compound reaching single digit nanomolar activity. Structure-activity relationship trends were evident and frontrunner compounds also displayed microsomal stability and favourable solubility profiles. Simplified synthetic routes support further derivatization of these compounds for further development of these series as malaria transmission-blocking agents.

Dialing in Direct Air Capture of CO2 by Crystal Engineering of Bisiminoguanidines.

Direct air capture (DAC) technologies that extract carbon dioxide from the atmosphere via chemical processes have the potential to restore the atmospheric CO2 concentration to an optimal level. This study elucidates structure-property relationships in DAC by crystallization of bis(iminoguanidine) (BIG) carbonate salts. Their crystal structures are analyzed by X-ray and neutron diffraction to accurately measure key structural parameters including molecular conformations, hydrogen bonding, and π-stacking. Experimental measurements of key properties, such as aqueous solubilities and regeneration energies and temperatures, are complemented by first-principles calculations of lattice and hydration free energies, as well as free energies of reactions with CO2, and BIG regenerations. Minor structural modifications in the molecular structure of the BIGs are found to result in major changes in the crystal structures and the aqueous solubilities within the series, leading to enhanced DAC.

Surprisingly selective sulfate extraction by a simple monofunctional di(imino)guanidinium micelle-forming anion receptor.

We report a novel di(imino)guanidinium anion extractant with unparalleled selectivity for sulfate in a liquid-liquid separation system. In addition to a 4.4 order-of-magnitude enhancement in affinity compared to a standard benchmark, our alkylated di(imino)guanidinium receptor is economically synthesized and features good compatibility with application-relevant aliphatic solvents. Small-angle X-ray scattering results reveal the formation of reverse-micelles, which together with the significant organic-phase water content challenge traditional notions of selectivity in extraction of superhydrophilic anions.