The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

Isothiourea HBTM-2.1 catalyses the Michael addition-lactonisation of 2-aryl and 2-alkenylacetic acids and α,β-unsaturated trichloromethyl ketones. Ring-opening of the resulting dihydropyranones and subsequent alcoholysis of the CCl3 ketone with an excess of methanol gives a range of diesters in high diastereo- and enantioselectivity (up to 95 : 5 dr and >99% ee). Sequential addition of two different nucleophiles to a dihydropyranone gives the corresponding differentially substituted diacid derivative.

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This review covers the methods that chemists have developed to access halogenated polycyclic structures from polyenes, by emulating Nature’s enzymatic machineries. From pioneering studies to the most recent developments, the different strategies, whether based on the use of standard reagents or on the design of specific ones, will be presented. Finally, asymmetric reactions and applications for the total synthesis of natural products will be exposed.1 Introduction2 Pioneering Studies3 Use of Specific Reagents4 Use of N-Haloamides5 Asymmetric Reactions6 Total Synthesis of Halogenated Natural Products7 Conclusion and Perspectives

Under basic conditions and heat, ynamides can serve as precursor to ketenimines, whose synthetic potential is often hampered by their difficulty of acces. Herein, we report that they can undergo a [3+2] cycloaddition with 2-azaallyl anions, obtained from benzylimines under the same reaction conditions. This reaction between two highly reactive intermediates, both generated in situ from bench stable starting materials, gives access to various nitrogen-rich heterocycles. The reaction usually proceeds with excellent diastereoselectivity, in favor of the cis adduct. Deuteration experiments and DFT calculation helped rationalize the regio and stereo-selectivity of the process as well as the formation of side-products..

The increasingly worrisome situation of antimicrobial resistances has pushed synthetic chemists to design original molecules that can fight these resistances. To do so, inhibiting β-lactamases, one of the main modes of resistance to β-lactam antibiotics, is one of the most sought-after strategies, as recently evidenced by the development and approval of avibactam, relabactam and vaborbactam. Yet molecules able to inhibit simultaneously β-lactamases belonging to different molecular classes remain scarce and currently there is no metallo-β-lactamase inhibitor approved for clinical use. Having recently developed a synthetic methodology to access imino-analogues of β-lactams (Chem. – Eur. J. 2017, 23, 12991,see ref) we decided to evaluate them as potential β-lactamase inhibitors and specifically against carbapenemases, which can hydrolyze and inactivate penicillins, cephalosporins and carbapenems. Herein we eport our findings that show that our newly developed family of molecules are indeed excellent β-lactamase inhibitors and that our lead compound can inhibit NDM-1 (0.1 µM), KPC-2 (0.4 µM), and OXA-48 (0.6 µM) even though these three enzymes belong to three different molecular classes of carbapenemases. This lead compound also inhibits the ESBL CTX-M-15 and the cephalosporinase CMY-2, it is metabolically stable, and can repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1.<br><br><br>

One approach for the synthesis of isoindolinones, a privileged bioactive heterocyclic core structure, involves a condensation reaction of o-phthaldialdehydes with a suitable nitrogencontaining nucleophile. This fascinating reaction is revisited here in the context of the use of o-phthaldialdehydes that contain additional substituents in the aromatic ring leading to a detailed analysis of the regioselectivity of the reaction. Eleven monosubstituted ophthaldialdehydes were synthesised and reacted with alanine. The regioselectivity observed across the eleven substrates led to the design of a disubstituted substrate that reacted with very high control. A gram-scale reaction followed by esterification gave one major regioisomer in high yield. In addition, the regioselectivity observed on reaction of two novel monodeuterated substrates led to an increased mechanistic understanding.

The original PDF version of this Article listed the authors as “Marcus J.G.W. Ladds,” where it should have read “Marcus J. G. W. Ladds, Ingeborg M. M. van Leeuwen, Catherine J. Drummond et al.#”.Also in the PDF version, it was incorrectly stated that “Correspondence and requests for materials should be addressed to S. Lín.”, instead of the correct “Correspondence and requests for materials should be addressed to S. Laín.”This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.