Medicinal Chemistry Research最新文献

Modeling non-covalent inhibitors of RAS oncoproteins has so far been carried out at whole molecule level, which left important molecular details hidden. Actually, for the endless process of improving the inhibitor performance, a more detailed knowledge of such interactions is desirable. The challenge has been taken in this work by disentangling the energies of interaction of KRAS-G12D-mutant residues with non-covalent inhibitors that, such as BI-2865 and MRTX1133, are currently on the limelight. In the lack of suitable experimental methodologies, the task has been addressed to molecular dynamics and quantum mechanics-molecular mechanics computer simulations. It emerged where, quantitatively at residue level, the inhibitor sticks better and where destabilizing repulsions arise. Moreover, for the newly appeared ternary complex of the non-covalent inhibitor RCM-6236 with cyclophilin A and KRAS G12R, a similar analysis gave also hints as to the mechanism of inhibition. Such detailed views offer clues as to improving the structure of the next generation non-covalent KRAS inhibitors.

The small-molecule MRTX1133 (in black stick) inhibits KRAS G12D mutant by digging, like an octopus, into the switch II motif of the receptor, where main stabilizing interactions are highlighted by interrupted lines.

A set of representative simple phosphinamides were synthesised and their physicochemical and metabolic properties were compared with matched pairs of benzamides and sulfonamides. We also synthesised phosphinamide analogues of some marketed drugs and compared the properties of the synthesised analogues with the known compounds. We found that phosphinamides have attractive physicochemical properties for incorporation into drug molecules, being lipophilicity lowering and generally solubility improving. Metabolic stabilities, hydrogen bond donor strengths and Caco-2 permeabilities of phosphinamides were similar to amide and sulfonamide analogues. The experimental polar surface area, surprisingly, showed a smaller difference between secondary and tertiary phosphinamides than for the corresponding benzamides and benzene sulfonamides. Chemical stability, however, is poor in acidic media and even on storage in DMSO solution and constitutes a significant liability for wider use of this functionality in medicinal chemistry.

Quorum sensing (QS) is the mechanism in which bacteria assess the threshold concentration of small signaling molecules to induce cell survival by overwhelming the host’s defenses. It is one of the fundamental mechanisms controlling bacterial mobility, motility, biofilm formation, and virulence. As many clinically resistant strains bypass traditional antimicrobial medications through this pathway, finding new therapeutics that target QS mechanisms is essential to treat these dangerous pathogens. Marine microbes are a promising source of potential therapeutics and have evolved molecules that can modulate disease-relevant signaling pathways, including QS. Compounds of various biosynthetic origin, including lipopeptides, alkaloids, cyclic peptides, and fatty acids have been shown to modulate QS pathways. In the present work, we have described the isolation, structure characterization, and biological evaluation of two new fatty acids, anaeic acid and tumoic acid. Anaeic acid (3) is a cyclopropanated fatty acid and shorter chain homologue of lyngbyoic acid (1). Tumoic acid (4) is the (6R)-methylated analogue of pitinoic acid A (2), characterized by a C-5 exo-double bond. The configurational assignment of 3 was conducted through analysis of the ¹H and 2D NMR to establish the trans configuration of the cyclopropane ring using the NOE correlations, and optical rotation was used to determine the absolute configuration of 3 compared to 1. The absolute configuration of 4 was established through chemical degradation and derivatization of the liberated secondary alcohol with a chiral auxiliary, followed by Mosher’s ester analysis. Both compounds were compared directly with their close cyanobacterial analogues 1 and 2, distinguished by different chain length and differences in methylation, and their unbranched counterparts to assess the impact of the substitution pattern on functional responses with respect to QS. Compounds 1-4 exhibited moderate QS inhibitory activity against Pseudomonas aeruginosa based on the reduced virulence factor production and transcriptional response. In contrast, unbranched fatty acid counterparts octanoic (5), decanoic acid (6) and lauric acid (7) showed a propensity to activate QS signaling, although this effect was only significantly manifested on the transcriptional level.

The p53–MDM2/MDMX interaction represents a pivotal therapeutic target in oncology, with the cis-imidazoline scaffold of Nutlin-3a serving as the first nanomolar small-molecule MDM2 antagonist. This comprehensive review traces the evolution of Nutlin derivatives from lead optimization to clinical translation. The structural modification section discusses rational strategies to enhance metabolic stability, solubility, and dual MDM2/MDMX inhibition, including the development of covalent inhibitors and PROTACs for targeted MDM2 degradation. The synthetic section details various synthetic approaches to Nutlins, integrating vicinal diamine formation, imidazoline ring construction, N-functionalization, and the nitro-Mannich reaction. Pharmacokinetic and pharmacodynamic profiling is explored, covering molecular target engagement and systemic distribution. The role of p53 status in specifying therapeutic efficacy is emphasized, along with discussion of synergistic combinations with over 60 agents. Preclinical proof-of-concept is presented across solid and hematological malignancies, with clinical validation in MDM2-amplified cancers and emerging evidence for non-oncological applications.

[¹¹C]COU is a trapped metabolite radiotracer for in vivo analysis of Monoamine Oxidase B activity using positron emission tomography (PET) imaging. [¹¹C]COU has the potential to quantify astrocytosis in the early stages of Alzheimer’s disease, providing an earlier marker of disease than currently available for staging disease progression. Prior preclinical studies have demonstrated the efficacy of this radiotracer in preclinical imaging studies, warranting the translation for clinical evaluation. In this paper, we describe results of the requisite preclinical studies required to obtain approval for translation of [¹¹C]COU into first-in-human studies. Development and validation of a production method that conforms to the quality requirements described in the US Pharmacopeia was accomplished, along with preclinical rodent studies to determine human radiation dose estimates and a single acute dose pharmacology and toxicology study to establish that an injected mass dose 100-fold higher than the proposed PET imaging dose was below the no-observed-adverse-effect level (NOAEL). The production method was validated in triplicate, yielding [¹¹C]COU in sufficient radiochemical yield (9.3 ± 0.008%), radiochemical purity (99.2 ± 0.002%) and molar activity (165 ± 65 TBq/mmol) for routine clinical use, and providing a product that was sterile and met (or exceeded) all quality control requirements for human use. Dosimetric analysis determined that the effective human dose of [¹¹C]COU is 0.005 mSv/MBq, also acceptable for clinical use. Lastly, no observable adverse effects were noted at 86 μg/kg in rodent toxicology studies (100x the proposed human dose). From these results we received approval to advance [¹¹C]COU into clinical studies.

Here, we report that long-term exposure of PANC-1 human pancreatic cancer cells to indirubin derivatives (Epox/5-Br-Ind) resulted in increased sensitivity to anticancer drugs such as 5-fluorouracil (5-FU) and gemcitabine (Gem). Epox/5-Br-Ind is an indirubin derivative bearing an oxirane moiety that is known to potently and continuously inhibit the proliferation of HepG2 liver cancer cells. We evaluated the effects of Epox/5-Br-Ind on PANC-1 proliferation from the perspectives of acute and chronic toxicity: acute toxicity was assessed using resazurin-based assays, while chronic toxicity was evaluated by comparing cumulative population doubling levels (CPDLs). Our results showed that Epox/5-Br-Ind compounds exhibited acute toxicity (IC₅₀ value = 1.8 μM) against PANC-1, but the concentration required to arrest cell proliferation over long-term exposure was only 0.1 μM. Flow cytometric analyses further revealed that chronic exposure to 0.1 μM Epox/5-Br-Ind induced a pronounced accumulation of cells in the S/G2/M phases and a clear increase in Annexin V–positive populations, indicating that sustained growth inhibition was accompanied by cell-cycle arrest and apoptosis induction. Results of docking simulations suggested that Epox/5-Br-Ind, like other indirubin derivatives, may inhibit the activity of common cyclin-dependent kinases (CDKs). Further analysis of gene expression profiles revealed time-dependent upregulation of Caspase-3 and -7 following exposure to Epox/5-Br-Ind, thereby paralleling CDK inhibition. However, we also observed concurrent upregulation of CDK2, suggesting a compensatory response to CDK4/6 inhibition. PANC-1 cells exposed to 0.1 μM Epox/5-Br-Ind for a prolonged period showed IC₅₀ values of 1.2 μM and 2.0 μM for 5-FU and Gem, respectively; these values were approximately 1/10 of the control group. Overall, our findings suggest that Epox/5-Br-Ind is a promising chemosensitizer and therapeutic candidate for combination treatment strategies to treat pancreatic cancer.

Lenacapavir is a first-in-class, long-acting HIV-1 capsid inhibitor and represents a significant advancement in both the treatment and prevention of HIV-1 infection. It is highly effective against both wild-type and multidrug-resistant strains of the virus. It has a unique mechanism of action involving the disruption of HIV-1 capsid assembly and nuclear import, which ultimately prevents the virus from integrating its genetic material into the host cell’s DNA and hinders viral replication. This review covers lenacapavir’s discovery and development, with a focus on its target validation, lead optimization, chemical synthesis, pharmacokinetic properties, safety profile, and clinical applications.