Synthesis Of Analogues Research Articles

Applications of biaryl cyclization in the synthesis of cyclic enkephalin analogs with a highly restricted flexibility

A series of 10 cyclic, biaryl analogs of enkephalin, with Tyr or Phe residues at positions 1 and 4, were synthesized according to the Miyaura borylation and Suzuki coupling methodology. Biaryl bridges formed by side chains of the two aromatic amino acid residues are of the meta–meta, meta–para, para–meta, and para–para configuration. Conformational properties of the peptides were studied by CD and NMR. CD studies allowed only to compare conformations of individual peptides while NMR investigations followed by XPLOR calculations provided detailed information on their conformation. Reliability of the XPLOR calculations was confirmed by quantum chemical ones performed for one of the analogs. No intramolecular hydrogen bonds were found in all the peptides. They are folded and adopt the type IV β-turn conformation. Due to a large steric strain, the aromatic carbon atoms forming the biaryl bond are distinctly pyramidalized. Seven of the peptides were tested in vitro for their affinity for the µ-opioid receptor.

Abstract 1252 Synthesis and Characterization of Novel Chemical Analogues to Detect Riboflavin (B2) Deficiency

Abstract 1252 Synthesis and Characterization of Novel Chemical Analogues to Detect Riboflavin (B2) Deficiency

Total Synthesis of Dynobactin A.

The first total synthesis of the potent antimicrobial agent dynobactin A is disclosed. This synthesis enlists a singular aziridine ring opening strategy to access the two disparate β-aryl-branched amino acids present within this complex decapeptide. Featuring a number of unique maneuvers to navigate inherently sensitive and epimerizable functional groups, this convergent approach proceeds in only 16 steps (LLS) from commercial materials and should facilitate the synthesis of numerous analogues for medicinal chemistry studies.

Synthesis of a Non-Symmetrical Disorazole C1-Analogue and Its Biological Activity.

The synthesis of a novel disorazole C1 analogue is described, and its biological activity as a cytotoxic compound is reported. Based on our convergent and flexible route to the disorazole core, we wish to report a robust strategy to synthesize a non-symmetrical disorazole in which we couple one half of the molecule containing the naturally occurring oxazole heterocycle and the second half of the disorazole macrocycle containing a thiazole heterocycle. This resulted in a very unusual non-symmetrical disorazole C1 analogue containing two different heterocycles, and its biological activity was studied. This provided exciting information about SAR (structure-activity-relationship) for this highly potent class of antitumor compounds.

Effect of some aspirin analogues on SW480 Colorectal cancer cell line: Tip of the iceberg

Abstract Colorectal cancer (CRC) is the third most common cancer and second leading cause of death with approximately 1.9 million cases and almost a million deaths worldwide in 2020. It is predicted that the global incidences of CRC will be over 3 million in 2040. Aspirin has been shown to have cytotoxic and immunomodulatory effects on CRC cell lines. However, due to side effects such as gastrointestinal bleeding in older patients, there has always a quest for safer and more effective analogues, leading to the synthesis of aspirin analogues. One of the primary regulators of the mitochondria-mediated pathway to apoptosis is the family known as BCL-2 proteins, which are broadly grouped into pro-apoptotic proteins such as BAX, BAK, BIK, BAD and anti-apoptotic proteins such as BCL-2 and BCL-XL. Phase contrast images of the SW480 CRC cells treated with aspirin, meta-aspirin, para-aspirin, ortho-thioaspirin, meta-thioaspirin and para-thioaspirin at 0.5 mM for 24 h, 48 h and 72 h were taken at 100X magnification. Western blot was used to detect BAX and BCL-2 proteins by treating CRC cells with aspirin and its analogues, and analysed by SDS-PAGE and immunoblotting. The blots were then probed with primary antibodies BCL-2 and BAX, after which the HRP bound protein-labelled antibody was visualised using ECL and exposed to CL-XPosure™ Film. It was observed that the isomers of aspirin (O-ASP), meta-aspirin (M-ASP) and para-aspirin (P-ASP) significantly increased the density of BAX Ab. O-ASP, M-ASP, P-ASP and ortho-thioaspirin (O-TASP) significantly reduced the density of BCL-2 Ab, thus proposing that the anti-apoptotic effect of this cell line is reversed/reduced by these aspirin analogues. The results of this study suggest that M-ASP and P-ASP have its antiproliferative effect on the SW480 CRC cell line via driving the pro-apoptotic effect of BAX protein and decreasing the expression of anti-apoptotic of BCL-2 protein, thus, encouraging apoptosis in this CRC cell line.

Design, synthesis and antibacterial assessment of novel 4H-chromene analogues

The significant medicinal and pharmacological facts about chromenes (benzopyran) nucleus prompted us to focus on constructing unique chromenes with biological value. New chromene derivatives 2–15 were synthesized, and their antibacterial effectiveness was studied. The reaction of the 2-amino-4H-chromene derivative 1 with a variety of reagents such as acetic anhydride, formic acid, chloroacetyl chloride, cyclopentanone, ethyl acetoacetate, diethyl malonate, aldehydes, and isatin produced derivatives 2–13. Compound 1 was also treated with aromatic amines such as p-toluidine and/or benzene-1,4-diamine with formaldehyde, yielding derivatives 14 and 15, respectively; spectral techniques were used to confirm the predicted structures of all compounds. The antibacterial activity of the recently synthesized compounds was assessed against two types of bacteria, Bacillus subtilis and Escherichia coli. There is encouraging antibacterial activity in compounds 5 and 7.

Synthesis and Biological Evaluation of vicinal-Diaryl Pyrazole Ethyl Carboxylate Analogs as Antiproliferative Agent against Pancreatic Cancer

vicinal Diaryl scaffold possessing various heterocycles displayed versatile pharmacological activities ranging from antibacterial to antiviral. Herein, the synthesis of novel vicinal diaryl pyrazole ethyl carboxylate analogs as central ring and evaluated for their antiproliferative activity against pancreatic cancer line, PANC-1. Among the synthesized 27 compounds, six compounds displayed the IC50 value for antiproliferative activity in single digit micromolar. The cytotoxicity results of the synthesized compounds especially compound 25 (IC50 = 4.8 µM) confirms that these analogs may require further investigation.

Development of a Water Soluble Self-assembling Analogue of Vizantin.

Vizantin, 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose, has been developed as a safe immunostimulator on the basis of a structure-activity relationship study with trehalose 6,6'-dicorynomycolate. Our recent study indicated that vizantin acts as an effective Toll-like receptor-4 (TLR4) partial agonist to reduce the lethality of an immune shock caused by lipopolysaccharide (LPS). However, because vizantin has low solubility in water, the aqueous solution used in in vivo assay systems settles out in tens of minutes. Here, vizantin was chemically modified in an attempt to facilitate the preparation of an aqueous solution of the drug. This paper describes the concise synthesis of a water-soluble vizantin analogue in which all the hydroxyl groups of the sugar unit were replaced by sulfates. The vizantin derivative displayed micelle-forming ability in water and potent TLR-4 partial agonist activity.

High‐Throughput Exploration of a Thioxanthone‐catalyzed Photoredox C−O Coupling

AbstractUsing High‐Throughput Experimentation (HTE), a visible light‐mediated etherification method was developed, employing the organic photocatalyst thioxanthen‐9‐one (TXO) and a commercially available, air‐stable nickel source. Design of Experiments (DoE) techniques were utilized in conjunction with HTE to identify optimal reaction conditions which are mild, cost‐effective, robust and therefore suitable for use in an industrial setting. A diverse substrate scope was prepared via parallel synthesis and selected examples were demonstrated on a 4.2 mmol scale in batch. Furthermore, the reaction was successfully performed on an 83 mmol scale, utilizing a standard jacketed reactor and Kessil PR160 L lamps.

Enantioselective Construction of C-SCF3 Stereocenters via Nickel Catalyzed Asymmetric Negishi Coupling Reaction.

The construction of the SCF3-containing 1,1-diaryl tertiary carbon stereocenters with high enantioselectivities is reported via a nickel-catalyzed asymmetric C-C coupling strategy. This method demonstrates simple operations, mild conditions and excellent functional group tolerance, with newly designed SCF3-containing synthon, which can be easily obtained from commercially available benzyl bromide and trifluoromethylthio anion in a two-step manner. Further substrate exploration indicated that the reaction system could be extended to diverse perfluoroalkyl sulfide (SC2F5, SC3F7, SC4F9, SCF2CO2Et)-substituted 1,1-diaryl compounds with excellent enantioselectivities. The synthetic utility of this transformation was further demonstrated by convenient derivatization to optical SCF3-containing analogues of bioactive compounds without an apparent decrease in enantioselectivity.

Discovery of the First‐in‐Class Inhibitors of Hypoxia Up‐Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation

AbstractFibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present a multidisciplinary lead discovery approach to identify and optimize small molecule inhibitors of pathogenic fibroblast activation. The study encompasses medicinal chemistry, molecular phenotyping assays, chemoproteomics, bulk RNA‐sequencing analysis, target validation experiments, and chemical absorption, distribution, metabolism, excretion and toxicity (ADMET)/pharmacokinetic (PK)/in vivo evaluation. The parallel synthesis employed for the production of the new benzamide derivatives enabled us to a) pinpoint key structural elements of the scaffold that provide potent fibroblast‐deactivating effects in cells, b) discriminate atoms or groups that favor or disfavor a desirable ADMET profile, and c) identify metabolic “hot spots”. Furthermore, we report the discovery of the first‐in‐class inhibitor leads for hypoxia up‐regulated protein 1 (HYOU1), a member of the heat shock protein 70 (HSP70) family often associated with cellular stress responses, particularly under hypoxic conditions. Targeting HYOU1 may therefore represent a potentially novel strategy to modulate fibroblast activation and treat chronic inflammatory and fibrotic disorders.

Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein 1 (HYOU1) Suppressing Pathogenic Fibroblast Activation.

Fibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present a multidisciplinary lead discovery approach to identify and optimize small molecule inhibitors of pathogenic fibroblast activation. The study encompasses medicinal chemistry, molecular phenotyping assays, chemoproteomics, bulk RNA-sequencing analysis, target validation experiments, and chemical absorption, distribution, metabolism, excretion and toxicity (ADMET)/pharmacokinetic (PK)/in vivo evaluation. The parallel synthesis employed for the production of the new benzamide derivatives enabled us to a) pinpoint key structural elements of the scaffold that provide potent fibroblast-deactivating effects in cells, b) discriminate atoms or groups that favor or disfavor a desirable ADMET profile, and c) identify metabolic "hot spots". Furthermore, we report the discovery of the first-in-class inhibitor leads for hypoxia up-regulated protein 1 (HYOU1), a member of the heat shock protein 70 (HSP70) family often associated with cellular stress responses, particularly under hypoxic conditions. Targeting HYOU1 may therefore represent a potentially novel strategy to modulate fibroblast activation and treat chronic inflammatory and fibrotic disorders.

Trifluoromethyl Rhodium-Carbynoid in [2+1+2] Cycloadditions.

Trifluoromethyl cationic carbyne (CF3 C+ :) possessing dual carbene-carbocation behavior emulated as trifluoromethyl metal-carbynoid (CF3 C+ =M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α-diazotrifluoroethyl sulfonium salt was prepared and used in Rh-catalyzed three-component [2+1+2] cycloadditions for the first time with commercially available N-fused heteroarenes and nitriles, yielding a series of imidazo[1,5-a] N-heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh-carbynoid (CF3 C+ =Rh) into C=N bonds of N-fused heteroarenes was involved. This strategy demonstrates synthetic applications in late-stage modification of pharmaceuticals, construction of CD3 -containing N-heterocycles, gram-scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5-a] N-heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

Targeting dihydroceramide desaturase 1 (Des1): Syntheses of ceramide analogues with a rigid scaffold, inhibitory assays, and AlphaFold2-assisted structural insights reveal cyclopropenone PR280 as a potent inhibitor

Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of PR280 as a better Des 1 inhibitor in vitro (IC50 = 700 nM) than GT11 and XM462, the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of GT11.

Current Strategies on the Enantioselective Synthesis of Modified Nucleosides

AbstractThe isolation of two carbocyclic nucleosides, viz., neplanocin A and aristeromycin, from natural sources, triggered a revolution in the scientific community, leading to the development of more versatile and therapeutically useful compounds. For this purpose, many new methods for the synthesis of the carbocyclic framework of nucleosides have been developed. These efforts resulted in the successful development of many marketable drugs. The inherent benefits associated with carbocyclic nucleosides, such as higher lipophilicity and metabolic stability, resistance against glycosidic hydrolysis and the ability to modify aromatic bases by cellular phosphorylases, make them popular for the development of drugs against cancer and different viruses. Classically, carbocyclic nucleosides of various ring sizes and configurations have been synthesized starting from chiral pool substrates, such as ribose, glucose, etc., but recently, many other new asymmetric versions have been developed. Herein, we present recent developments on the catalytic enantioselective synthesis of nucleoside analogues, including carbocyclic and other varieties. This account provides new insights into the future development of modified nucleosides.1 Introduction2 Cyclic Nucleosides3 Acyclic Nucleosides4 Conclusion

Trifluoromethyl Rhodium‐Carbynoid in [2+1+2] Cycloadditions

AbstractTrifluoromethyl cationic carbyne (CF3C+:) possessing dual carbene‐carbocation behavior emulated as trifluoromethyl metal‐carbynoid (CF3C+=M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α‐diazotrifluoroethyl sulfonium salt was prepared and used in Rh‐catalyzed three‐component [2+1+2] cycloadditions for the first time with commercially available N‐fused heteroarenes and nitriles, yielding a series of imidazo[1,5‐a] N‐heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh‐carbynoid (CF3C+=Rh) into C=N bonds of N‐fused heteroarenes was involved. This strategy demonstrates synthetic applications in late‐stage modification of pharmaceuticals, construction of CD3‐containing N‐heterocycles, gram‐scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5‐a] N‐heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

(4Z)-Lachnophyllum Lactone, a Metabolite with Phytotoxic and Antifungal Activity against Pests Affecting Mediterranean Agriculture: A New Versatile and Easy Scalable Parallel Synthesis.

A methodology for the total and modulable synthesis of (4Z)-lachnophyllum lactone (1), on a gram scale, is reported for the first time. The present work started with the design of a retrosynthetic pathway for the target compound, with the key step identified in Pd-Cu bimetallic cascade cross-coupling cyclization. (4Z)-Lachnophyllum lactone (1) is an acetylenic furanone previously isolated, in a low amount, from the organic extract of the autotrophic weedConyza bonariensis. Tested against the stem parasitic weed Cuscuta campestris in a seedling growth bioassay, (4Z)-lachnophyllum lactone (1) showed almost 85% of inhibitory activity up to 0.3 mM in comparison with the control. At the same concentration, the compound displayed radicle growth inhibitory activity of the root parasitic weeds Orobanche minor and Phelipanche ramosa higher than 70 and 40%, respectively. Surprisingly, the compound showed a high percentage of inhibition, up to 0.1 mM, on C. bonariensis seed germination too. This versatile synthetic strategy was also used to obtain two further natural analogues, namely, (4E)-lachnophyllum lactone (8) and (4Z,8Z)-matricaria lactone (9), that showed, in most cases, the same inhibitory trend with slight differences, highlighting the importance of the stereochemistry and unsaturation of the side chain. Furthermore, all of the compounds showed antifungal activity at 1 mM reducing the mycelial growth of the olive pathogen Verticillium dahliae. The design and implementation of scalable and modulable total synthesis on a gram scale of acetylenic furanones allow the production of a large amount of these natural products, overcoming the limit imposed by isolation from natural sources. The results of the present study pave the way for the development of ecofriendly bioinspired pesticides with potential application in agrochemical practices as alternative to synthetic pesticides.

An overview of synthetic approaches and the potential bioactivity of different 1,2,3-triazole hybrids

1,2,3-Triazole is considered to be the lead structure for the discovery of many drug molecules. 1,2,3-Triazole has received considerable attention in the field of drug discovery due to its remarkable widespread biological potential. This work summarizes the current synthetic pathways adopted for the synthesis of diverse analogs of 1,2,3-triazole. It also introduces an overview of the latest advances in 1,2,3-triazole hybrid models with various pharmacological activities, their chemical structures, structure–activity relationships, and mechanisms of action.

Design, synthesis, and evaluation of cyclic C7-bridged monocarbonyl curcumin analogs containing an o-methoxy phenyl group as potential agents against gastric cancer

The structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an o-methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model (R 2 > 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited in vitro and in vivo anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable in vivo safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.

SNAr or Sulfonylation? Chemoselective Amination of Halo(het)arene Sulfonyl Halides for Synthetic Applications and Ultralarge Compound Library Design.

The chemoselectivity of halo(het)arene sulfonyl halide aminations is studied thoroughly under parallel synthesis conditions, and the scope and limitations of the method are established. It is shown that SNAr-reactive sulfonyl halides typically undergo sulfonamide synthesis during the first step; the second amination is also possible provided that the SNAr-active center is sufficiently reactive. On the contrary, sulfonyl fluorides bearing an arylating moiety undergo selective transformation at the latter reactive center under proper control. Further sulfur-fluoride exchange (SuFEx) is also possible, which can be especially valuable for some sulfonyl halide classes. The developed two-step parallel double amination protocol provides access to a 6.67-billion compound synthetically tractable REAL-type chemical space (76% expected synthesis success rate).