Gagan Kukreja’s Post

Having explored piperazines and piperidines, it's difficult to resist trying Morpholines while fine tuning SAR, be it in Medchem or AgChem. However what comes as an obstacle are the efficient synthetic methods when starting from 1,2-amino alcohols. Coming with many environmental and safety benefits relative to the traditional methods used to prepare morpholines from 1,2-amino alcohols, now a new methodology reports a simple, high yielding, one or two-step, redox neutral protocol using inexpensive reagents (ethylene sulfate and tBuOK) for the conversion of 1,2-amino alcohols to morpholines. Key to this methodology lies in the identification of general conditions that allows the clean isolation of monoalkylation products derived from a simple SN2 reaction between primary amines and ethylene sulfate. Reported 28 examples derived from primary amines and multiple examples contained in known active pharmaceutical ingredients, demonstrates the versatility of the method to synthesize a variety of morpholines containing substituents at various positions. What more, the publication reports multiple examples on >50 g scale as well! https://lnkd.in/gFN4qRt3

Synthesis and Functionalization of SulfoximineBicyclo[1.1.0]butanes: Functionalizable, Tuneable and CysteineSelective Chiral Warheads The present work reports an efficient one-pot synthesis of series of sulfoximine bicyclo[1.1.0]butanes (BCBs) as novel thiol reactive chiral warheads, achieved from methylsulfoximines, demonstrating selective strain-release reactivity towards cysteine nucleophiles under biocompatible conditions. Preliminary publication data indicates suitability for chemoproteomic applications, and enantioselective cysteine-labelling, wherein the reactivity of sulfoximine BCBs with electron withdrawing groups on nitrogen is comparable to acrylamides with low to moderate reactivity. The BCB bridgehead functionalization and aryl cross-coupling reactions hold promise to allow rapid diversification and fragment growth, and also facilitate their incorporation into screening collections. https://lnkd.in/gn8SNgMz

Renaissance of iron-catalysed carbon–carbon bond-forming transformations with soft nucleophilic coupling partners. When it comes to Suzuki coupling, there is an increasing desire to replace Palladium metal with a more sustainable, less expensive alternative, with catalysts based on nickel, copper, cobalt and Iron. Among these, Iron represents the ideal first-row transition metal for replacing palladium in Suzuki biaryl cross-coupling reactions as it is very cheap, widely available and relatively non-toxic. However, the currently reported iron-catalysed Suzuki biaryl cross-couplings under synthetically reasonable conditions require either an activated heteroaryl substrate or the use of substrate-directed C–X activation. The present work describes the use of a simple iron-based catalyst with an N-heterocyclic carbene ligand for carrying out the Suzuki biaryl coupling of aryl chloride substrates with aryl boronic esters activated by an organolithium reagent. While issues remain associated with competitive homo-coupling, the results reported here demonstrate that this synthetically challenging—for iron—yet highly desirable transformation is achievable and can accommodate a good range of coupling partners. Mechanistic studies suggest the possible involvement of Fe(I) as the lowest oxidation state on the catalytic manifold and show that the challenging step is not activation of the aryl chloride substrate, but rather the transmetallation step https://lnkd.in/gkKVe6mu

How about having the best of both worlds together - pyrroloindoline core decorated with a N–CF3 moiety, where both, the building block and the functional group individually holds a significant importance in medicinal chemistry. In fact over the years there is a growing interest in the bioactive molecules featuring N–CF3 moieties from the medicinal chemistry community where the introduction of the trifluoromethyl (CF3) group has been widely utilized to adjust the biophysical properties of small molecules, such as lipophilicity, permeability, and metabolic stability. However, the lack of efficient and straightforward methods to prepare N–CF3-containing compounds continues to remain a significant limitation, in particular with no reported synthesis of constructing N–CF3-containing pyrroloindolines reported till date. The new methodology presents a robust and operationally simple approach to assembling such intriguing skeletons from tryptamine-derived isocyanides through a cascade sequence, which includes an oxidative trifluorination and a subsequent halogenative cyclization. The key to the success lies in the development of a facile, operationally simple conversion of isocyanides to N–CF3 moiety with commercially available reagents N-halosuccinimide and Et3N·HF The protocol features mild reaction conditions, broad functional group tolerance, good to excellent yields and high diastereoselectivity. Importantly, the halide functionality within the products enables rapid access to diverse C3-quaternary-substituted N–CF3-containing pyrroloindolines. Given the synthetic practicality, the method developed herein has good chances to find more valuable applications in medicinal chemistry. https://lnkd.in/gDgKZEaZ

A new photoinduced vitamin-B12-catalyzed meta-C–H bromination/chlorination of phenol derivatives using nitrile directing template and N-bromosuccinimide (NBS)/N-chlorosuccinimide (NCS) as halogenated reagents, overcomes the selectivity problem of phenols, in obtaining meta-products through conventional electrophilic reactions. The testimony of the practicability of this method is signified by the successful synthesis of natural product resveratrol and an intermediate of the γ-secretase inhibitor. https://lnkd.in/gMsMpJK9

Exploration of α-triazolylboronic acids as a novel scaffold for targeting FLT3 in AML, however single-agent FLT3 inhibitor therapy has yielded unsatisfactory clinical results thus far. Boronic acids represent an intriguing and unexplored class of compounds in the context of AML and only few examples report boronic acids as PKI, whereas the incorporation of the boronic group has demonstrated to enhance the bioavailability and pharmacokinetic profile of other conventional anticancer drugs. The most promising inhibitor from this study, 4g shows low micromolar activities on enzymatic and cellular assays, selectivity against control cell lines and a recurring binding mode in in-silico studies. Importantly, control compounds synthesized ad-hoc indicates that the activity of the scaffold is linked to the presence of the boronic acid moiety. α-triazolylboronic acids were easily synthesized by click chemistry from readily available precursors, with few purification issues. https://lnkd.in/gqF8vvRy

The emerging limitations of advanced algorithms and ML techniques are somewhere falling short to keep up with the hype of yielding substantial improvements in the field of small-molecule drug discovery to make a significant leap forward. This below perspective proposes to put more efforts to focus on the data for training and benchmarking these models which is more likely to drive future improvement, and explore strategies to address these data challenges.

Raising the curtains to ZLC491, the first orally bioavailable PROTAC degrader of CDK12/13 ZLC491 effectively degrades CDK12 and CDK13 with DC50 values of 32 and 28 nM, respectively, in TNBC MDA-MB-231 cells. Global proteomic assessment and mechanistic studies revealed that ZLC491 selectively induced CDK12/13 degradation in a cereblon- and proteasome-dependent manner. Furthermore, the molecule efficiently suppressed transcription and expression of long genes, predominantly a subset of genes associated with DNA damage response, and significantly inhibited proliferation of multiple TNBC cell lines. Importantly, ZLC491 demonstrates potent in vivo degradative effects on CDK12/13 in an MDA-MB-231 xenografted mouse model. https://lnkd.in/g8C6bCNR

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Identifying a crucial binding site on its surface, a new study tricks the tricky-to-target cancer-related protein called Forkhead box protein 1 (FOXA1), a master regulator of gene control by discovering chemical probes for historically been considered an "undruggable" target What makes this discovery special is finding a small molecule binding site on transcription factors like FOXA1 which has the binding sits which act like a hidden lock. Thanks to chemical proteomic methods such as activity-based protein profiling (ABPP) technology that allowed the global mapping of small-molecule-protein interactions directly in native biological systems to pinpoint the exact binding site. Contrary to what is originally thought, the researchers found that small molecules couldn’t just attach to FOXA1 on their own. Instead, they could only bind to FOXA1 when the protein was already bound to DNA sequences—meaning the effectiveness of small molecules as cancer treatments probably relies on FOXA1’s interactions with DNA. Going ahead, the researchers plan to explore the optimization of FOXA1 ligands into antagonists of its function and cancer growth, as well as to use ABPP to search for small molecule binding sites on transcription factors beyond FOXA1 that are currently considered undruggable. https://lnkd.in/grNvHjyF https://lnkd.in/gMf_UYAQ