The abnormal levels of the human carbonic anhydrase isoenzymes I and II (hCA I and II) and cholinesterase enzymes, namely, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are linked with various disorders including Alzheimer’s disease. In this study, six new nicotinic hydrazide derivatives (7–12) were designed and synthesized for the first time, and their inhibitory profiles against hCA I, hCA II, AChE, and BChE were investigated by in vitro assays and in silico studies. The structures of novel molecules were elucidated by using spectroscopic techniques and elemental analysis. These molecules showed inhibitory activities against hCA I and II with IC50 values ranging from 7.12 to 45.12 nM. Compared to reference drug acetazolamide (AZA), compound 8 was the most active inhibitor against hCA I and II. On the other hand, it was determined that IC50 values of the tested molecules ranged between 21.45 and 61.37 nM for AChE and between 18.42 and 54.74 nM for BChE. Among them, compound 12 was the most potent inhibitor of AChE and BChE, with IC50 values of 21.45 and 18.42 nM, respectively. In order to better understand the mode of action of these new compounds, state-of-the-art molecular modeling techniques were also conducted.

Synthesis of Novel Hydrazide–Hydrazone Compounds and In Vitro and In Silico Investigation of Their Biological Activities against AChE, BChE, and hCA I and II

Our skin protects us from external threats including ultraviolet radiation, pathogens and chemicals, and prevents excessive trans-epidermal water loss. These varied activities are reliant on a vast array of lipids, many of which are unique to skin, and that support physical, microbiological and immunological barriers. The cutaneous physical barrier is dependent on a specific lipid matrix that surrounds terminally-differentiated keratinocytes in the stratum corneum. Sebum- and keratinocyte-derived lipids cover the skin's surface and support and regulate the skin microbiota. Meanwhile, lipids signal between resident and infiltrating cutaneous immune cells, driving inflammation and its resolution in response to pathogens and other threats. Lipids of particular importance include ceramides, which are crucial for stratum corneum lipid matrix formation and therefore physical barrier functionality, fatty acids, which contribute to the acidic pH of the skin surface and regulate the microbiota, as well as the stratum corneum lipid matrix, and bioactive metabolites of these fatty acids, involved in cell signalling, inflammation, and numerous other cutaneous processes. These diverse and complex lipids maintain homeostasis in healthy skin, and are implicated in many cutaneous diseases, as well as unrelated systemic conditions with skin manifestations, and processes such as ageing. Lipids also contribute to the gut-skin axis, signalling between the two barrier sites. Therefore, skin lipids provide a valuable resource for exploration of healthy cutaneous processes, local and systemic disease development and progression, and accessible biomarker discovery for systemic disease, as well as an opportunity to fully understand the relationship between the host and the skin microbiota. Investigation of skin lipids could provide diagnostic and prognostic biomarkers, and help identify new targets for interventions. Development and improvement of existing in vitro and in silico approaches to explore the cutaneous lipidome, as well as advances in skin lipidomics technologies, will facilitate ongoing progress in skin lipid research. 

Bioactive lipids in the skin barrier mediate its functionality in health and disease

The total syntheses of selected natural products using different versions of the Ugi multicomponent reaction is reviewed on a case-by-case basis. The revision covers the period 2008-2023 and includes detailed descriptions of the synthetic sequences, the use of state-of-the-art chemical reagents and strategies, as well as the advantages and limitations of the transformation and some remedial solutions. Relevant data on the isolation and bioactivity of the different natural targets are also briefly provided. The examples clearly evidence the strategic importance of this transformation and its key role in the modern natural products synthetic chemistry toolbox. This methodology proved to be a valuable means for easily building molecular complexity and efficiently delivering step-economic syntheses even of intricate structures, with a promising future.

Recent developments in the total synthesis of natural products using the Ugi multicomponent reactions as the key strategy.

Solid-Phase Total Synthesis of Sandramycin and Its Analogues.

Synthetic analogs based on the DNA bis-intercalating natural product peptides sandramycin and quinaldopeptin were investigated as antibody drug conjugate (ADC) payloads. Synthesis, biophysical characterization, and in vitro potency of 34 new analogs are described. Conjugation of an initial drug-linker derived from a novel bis-intercalating peptide produced an ADC that was hydrophobic and prone to aggregation. Two strategies were employed to improve ADC physiochemical properties: addition of a solubilizing group in the linker and the use of an enzymatically cleavable hydrophilic mask on the payload itself. All ADCs showed potent in vitro cytotoxicity in high antigen expressing cells; however, masked ADCs were less potent than payload matched unmasked ADCs in lower antigen expressing cell lines. Two pilot in vivo studies were conducted using stochastically conjugated DAR4 anti-FRα ADCs, which showed toxicity even at low doses, and site-specific conjugated (THIOMAB) DAR2 anti-cMet ADCs that were well tolerated and highly efficacious.

Structure-Activity Relationships of Bis-Intercalating Peptides and Their Application as Antibody-Drug Conjugate Payloads.

Solid-Phase Total Synthesis of Plusbacin A3.

Summary Protein-bound ceramides, specialized ceramides covalently bound to corneocyte surface proteins, are essential for skin permeability barrier function. However, their exact structure and target amino acid residues are unknown. Here, we found that epoxy-enone (EE) ceramides, precursors of protein-bound ceramides, as well as their synthetic analog, formed stable conjugates only with Cys among nucleophilic amino acids. NMR spectroscopy revealed that the β-carbon of the enone was attached by the thiol group of Cys via a Michael addition reaction. We confirmed the presence of Cys-bound EE ceramides in mouse epidermis by mass spectrometry analysis of protease-digested epidermis samples. EE-ceramides were reversibly released from protein-bound ceramides via sulfoxide elimination. We found that protein-bound ceramides with reversible release properties accounted for approximately 60% of total protein-bound ceramides, indicating that Cys-bound EE ceramides are the predominant protein-bound ceramides. Our findings provide clues to the molecular mechanism of skin barrier formation by protein-bound ceramides. Highlights Epoxy-enone (EE) ceramides form stable conjugates with Cys. Cys binds to the β-carbon of the enone via a Michael addition reaction. Cys-bound EE ceramides exist in the mouse epidermis. Cys-bound EE ceramides are the predominant protein-bound ceramides. In Brief Protein-bound ceramides are specialized ceramides essential for skin permeability barrier function. In the present study, we determined the exact structure of protein-bound ceramides as Cys-bound epoxy-enone ceramides where the β-carbon of the epoxy-enone ceramides is attached by Cys residues of corneocyte surface proteins via a Michael addition reaction. 

Determining the structure of protein-bound ceramides, essential lipids for skin barrier function

Solid-phase total synthesis of nannocystin Ax (1) was disclosed. A coupling reaction between a peptide and a polyketide moiety was conducted on a solid support, and macrocyclization was achieved by Mitsunobu cyclization. The established synthetic route was efficient to prepare its analogues, which contain different types of peptide moieties.

Solid-Phase Synthesis of Nannocystin Ax and Its Analogues.

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death, thus a novel chemotherapeutic agent for colon cancer therapy is needed. In this study, analogues of echinomycin, a cyclic peptide natural product with potent toxicity to several human cancer cell lines, were synthesized, and their biological activities against human colon cancer cells were investigated. Analogue 3 as well as 1 inhibit HIF-1α-mediated transcription. Notably, transcriptome analysis indicated that the cell cycle and its regulation were involved in the effects on cells treated with 3. Analogue 3 exhibited superior in vivo efficacy to echinomycin without significant toxicity in mouse xenograft model. The low dose of 3 needed to be efficacious in vivo is also noteworthy and our data suggest that 3 is an attractive and potentially novel agent for the treatment of colon cancer. 

Synthesis and biological evaluation of echinomycin analogues as potential colon cancer agent

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