Semisynthetic Analogues Research Articles

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

In-Vitro and In-Silico Studies of Brevifoliol Ester Analogues against Insulin Resistance Condition.

Brevifoliol is a diterpenoid that occurs naturally in the plants of Taxus genus and is widely used as chemotherapy agent for the management of cancer. A series of semisynthetic esters analogues of brevifoliol were prepared by Steglich esterification and attempted for their pharmacological potential against insulin resistance conditions using in-vitro and in-silico assays. The aim of this study is to understand the pharmacological potential of eighteen semisynthetic analogs through Steglich esterification of Brevifoliol against insulin resistance condition Methods: In the in-vitro study, insulin resistance condition was induced in skeletal muscle cells using TNF-α, pro-inflammatory cytokine and these cells were treated with brevifoliol analogues. The most potent analouge was further validated using in-silico docking study against the tumor necrosis factor (TNF-α) (PDB ID: 2AZ5) and Human Insulin Receptor (PDB ID: 1IR3), using the Auto dock Vina v0.8 program. Although, all the analogues of Brevifoliol significantly exhibited the pharmacological potential. Among all, analogue 17 was most potent in reversing the TNF-α induced insulin resistance condition in skeletal muscle cells and also to inhibit the production of TNF-α in LPSinduced inflammation in macrophage cells in a dose-dependent manner. Similarly, in-silico molecular docking studies revealed that analogue 17 possesses a more promising binding affinity than the selected control drug metformin toward the TNF-α and insulin receptor. These findings suggested the suitability of analogue 17 as a drug-like candidate for further investigation toward the management of insulin resistance conditions.

Anti-neoplastic Properties of Boswellic Acids and their Novel Semi-synthetic Analogs: In vitro, In vivo and Clinical Evidence

Introduction: Recently, Boswellia gum resin extract has been shown to exhibit therapeutic properties against multiple inflammatory illnesses, comprising arthritis, asthma, diabetes, inflammatory bowel disease, and different malignancies. There are growing shreds of evidence that Boswellia extracts and their phytoconstituents could be used in adjuvant and combinatorial chemotherapeutic approaches for the management and prevention of cancer. Aim: The principal objective of this comprehensive investigation is to offer up-to-date and in-depth insights into the anticancer potential of boswellic acids along with their semisynthetic analog that are novel and preventive/therapeutic substitutes for the management of cancer and inflammatory diseases due to their strong potential. Materials and Methods: In the course of this review, a comprehensive compilation of In-vitro, Invivo, and clinical evidence on the antineoplastic potential of boswellic acids was assembled through systematic computerized searches utilizing platforms such as Google Scholar, PubMed, Sci-Hub, and Research Gate. Result: Boswellic acids, the key compounds found in the resin of nearly all the species of the Boswellia plant, have been reported to exhibit therapeutic effects by modulating various targets in different disease conditions. Moreover, semisynthetic derivatives of boswellic acids show strong cytotoxic effects, particularly those with cyanoenone moieties, endoperoxides, and hybrids, which exhibit enhanced potency. Conclusion: In this review, we have sincerely highlighted the effectiveness of novel boswellic acids as alternative preventive and therapeutic agents for the treatment of cancer and inflammatory conditions. Their strong anticancer potential could provide a basis for promising future direction to develop potent anticancer drugs for human malignancies.

Chlorophyll Pigments and Their Synthetic Analogs.

Oxygenic phototrophs use chlorophylls (Chls) as photosynthetically active pigments. A variety of Chl molecules have been found in photosynthetic eukaryotes including green plants, algae, and cyanobacteria. Here we review their molecular structures with stereochemistry, occurrence in light-harvesting antennas and reaction centers, biosyntheses in the late stage, chemical stabilities, and visible absorption maxima in diethyl ether. The observed maxima are comparable to those of semisynthetic Chl analogs, methyl pyropheophorbides, in dichloromethane. The effects of their peripheral substituents and core π-conjugation on the maxima of the monomeric states are discussed. Notably, the oxidation along the molecular x-axis in Chl-a produces its accessory pigments, Chls-b/c, and introduction of an electron-withdrawing formyl group along the y-axis perpendicular to the x-axis affords far-red light absorbing Chls-d/f.

The Usnic Acid Analogue 4-FPBUA Enhances the Blood-Brain Barrier Function and Induces Autophagy in Alzheimer's Disease Mouse Models.

Preclinical and clinical studies have indicated that compromised blood-brain barrier (BBB) function contributes to Alzheimer's disease (AD) pathology. BBB breakdown ranged from mild disruption of tight junctions (TJs) with increased BBB permeability to chronic integrity loss, affecting transport across the BBB, reducing brain perfusion, and triggering inflammatory responses. We recently developed a high-throughput screening (HTS) assay to identify hit compounds that enhance the function of a cell-based BBB model. The HTS screen identified (S,E)-2-acetyl-6-[3-(4'-fluorobiphenyl-4-yl)acryloyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo-[b,d]furan-1(9bH)-one (4-FPBUA), a semisynthetic analogue of naturally occurring usnic acid, which protected the in vitro model against Aβ toxicity. Usnic acid is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton that is commonly found in lichenized fungi of the genera Usnea. In this study, we aimed to evaluate the effect of 4-FPBUA in vitro on the cell-based BBB model function and its in vivo ability to rectify BBB function and reduce brain Aβ in two AD mouse models, namely, 5xFAD and TgSwDI. Our findings demonstrated that 4-FPBUA enhanced cell-based BBB function, increased Aβ transport across the monolayer, and reversed BBB breakdown in vivo by enhancing autophagy as an mTOR inhibitor. Induced autophagy was associated with a significant reduction in Aβ accumulation and related pathologies and improved memory function. These results underscore the potential of 4-FPBUA as a candidate for further preclinical exploration to better understand its mechanisms of action and to optimize dosing strategies. Continued research may also elucidate additional pathways through which 4-FPBUA contributed to the amelioration of BBB dysfunction in AD. Collectively, our findings supported the development of 4-FPBUA as a therapeutic agent against AD.

Synthesis and Structural Activity Relationship Study of Ursolic Acid Derivatives as Antitubercular Agent.

The chemical transformation of ursolic acid (UA) into novel C-3 aryl ester derivatives and in vitro and silico assessment of their antitubercular potential. UA is a natural pentacyclic triterpenoid with many pharmacological properties. Semisynthetic UA analogs have demonstrated enhanced anticancer, antimalarial, and antifilarial properties in our previous studies. The C-30 carboxylic group of previously isolated UA was protected, and various C-3 aryl ester derivatives were semi-synthesized. The agar dilution method was used to evaluate the in vitro antitubercular efficacy of Mycobacterium tuberculosis (Mtb) H37Ra. In silico docking studies of the active derivative were carried out against Mtb targets, catalase peroxidase (PDB: 1SJ2), dihydrofolate reductase (PDB: 4M2X), enoyl-ACP reductase (PDB: 4TRO), and cytochrome bc1 oxidase (PDB: 7E1V). The derivative 3-O-(2-amino,3-methyl benzoic acid)-ethyl ursolate (UA-1H) was the most active among the eight derivatives (MIC1 2.5 μg/mL) against Mtb H37Ra. Also, UA-1H demonstrated significant binding affinity in the range of 10.8-11.4 kcal/mol against the antiTb target proteins, which was far better than the positive control Isoniazid, Ethambutol, and co-crystallized ligand (HEM). Moreover, the predicted hit UA-1H showed no inhibition of Cytochrome P450 2D6 (CYP2D6), suggesting its potential for favorable metabolism in Phase I clinical studies. The ursolic acid derivative UA-1H possesses significant in vitro antitubercular potential with favorable in silico pharmacokinetics. Hence, further in vivo assessments are suggested for UA-1H for its possible development into a secure and efficient antitubercular drug.

Oxidation Study of Oleocanthal and Oleacein Induced by Oxone

AbstractA selective Oxone-induced oxidation of oleocanthal and oleacein, the two main secoiridoids of olive oil, to their bis-oxidized products is described. This protocol is based on a Baeyer-Villiger mechanism and the concentration of Oxone in the final solution. The bis-oxidation of the aldehydic compounds could be extended for the synthesis of various semisynthetic analogs. The obtained acids exhibit strong antioxidant activity, being efficient free radical scavengers.

Isolation of Fidaxomicin and Shunt Metabolites from Actinoplanes deccanensis

AbstractA protocol for the isolation of the antibiotic fidaxomicin (Fdx) from Actinoplanes deccanensis and the isolation of shunt metabolites from A. deccanensis fdxG2− is reported. We constructed the mutant strain A. deccanensis fdxG2− by genetic manipulation which enabled the isolation of shunt metabolites as useful starting points for semisynthetic analogues of Fdx. Furthermore, a synthetic protocol for the conversion of complex A. deccanensis fdxG2− extracts into the single compound FdxG2‐OH via methanolysis is presented. This synthetic procedure is complemented by images and practical notes. Full structure assignment is given in the SI and the characterization data files are published to aid experimentalists. The protocol is also suitable as an undergraduate laboratory project. We hope to facilitate research into new Fdx derivatives through the availability of this procedure.

Anticancer Effects of Abietane Diterpene 7α-Acetoxy-6β-hydroxyroyleanone from Plectranthus grandidentatus and Its Semi-Synthetic Analogs: An In Silico Computational Approach.

The abietane diterpenoid 7α-acetoxy-6β-hydroxyroyleanone (Roy) isolated from Plectranthus grandidentatus demonstrates cytotoxicity across numerous cancer cell lines. To potentiate anticancer attributes, a series of semi-synthetic Roy derivatives were generated and examined computationally. ADMET predictions were used to evaluate drug-likeness and toxicity risks. The antineoplastic potential was quantified by PASS. The DFT models were used to assess their reactivity and stability. Molecular docking determined cancer-related protein binding. MS simulations examined ligand-protein stability. Additionally, network pharmacology was used to identify potential targets and signaling pathways. Favorable ADME attributes and acceptable toxicity profiles were determined for all compounds. Strong anticancer potential was shown across derivatives (Pa 0.819-0.879). Strategic modifications altered HOMO-LUMO gaps (3.39-3.79 eV) and global reactivity indices. Favorable binding was revealed against cyclin-dependent kinases, BCL-2, caspases, receptor tyrosine kinases, and p53. The ligand exhibited a stable binding pose in MD simulations. Network analysis revealed involvement in cancer-related pathways. In silico evaluations predicted Roy and derivatives as effective molecules with anticancer properties. Experimental progress is warranted to realize their chemotherapeutic potential.

Exploring the potential of semi-synthetic Swertiamarin analogues for GLUT facilitation and insulin secretion in NIT-1 cell lines: a molecular docking and in-vitro study

Synthesis, characterisation, and anti-diabetic potential of swertiamarin analogues against DPP-4 enzymatic inhibition was done prior to this study. However, swertiamarin and its analogues inhibited DPP-4 enzyme significantly. Semisynthetic swertiamarin analogues have been studied for antidiabetic potential and mechanism of action utilising molecular docking and in-vitro techniques. The mechanism of action for swertiamarin analogues was determined by in-silico molecular docking studies using glucose-transporters, GLUT-1 (PDB ID: 4PYP), GLUT-3 (PDB ID: 7SPS), and GLUT-4 (PDB ID: 7WSM) along with in-vitro glucose uptake and glucose-induced insulin secretion assays. These studies found that synthesised swertiamarin analogues SNIPERSV3, SNIPERSV4, and SNIPERSV7 shown better docking score against different GLUTs and better anti-diabetic effects on glucose uptake and insulin secretion in NIT-1 cell line than standard glibenclamide and swertiamarin. Thus, swertiamarin analogues might be studied for diabetes therapy in the future.

Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), MTZ, a newly employed ETC complex I inhibitor, exhibited higher cytotoxicity against cancer cell lines compared to certain non-cancer cell lines. Interestingly, 8-OAc demonstrated greater selectivity for cancer cells when compared to both MTZ and Rote, which has promising potential for anticancer therapeutic development. Furthermore, in vivo experiments with these small molecules utilizing a C. elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPRMT) pathway, that extends lifespan of worms when applied in their adult stage. We also found that these two molecules employ different pathways to extend lifespan in worms. Whereas MTZ utilizes the transcription factors ATFS-1 and HSF1, which are involved in the UPRMT and heat shock response (HSR) pathways respectively, 8-OAc only required HSF1 and not ATFS-1 to mediate its effects. This observation underscores the value of applying stable, potent, and selective next generation chemical probes to elucidate an important insight into the functional roles of various protein subunits of ETC complexes and their regulatory mechanisms associated with aging.

LC-MS/MS analysis of 11-nor-9-carboxy-hexahydrocannabinol (HHC-COOH) and 11-hydroxy-hexahydrocannabinol (HHC-OH) for verification of hexahydrocannabinol (HHC) intake

Natural and semi-synthetic cannabinoid analogs are getting increasing media attention for their recreative use as an alternative to traditional cannabis, in Sweden as well as internationally. To investigate an increasing number of urine samples incoming to our clinical laboratory that were screening positive, using a CEDIA THC-COOH immunoassay from ThermoFisher Scientific, but then testing negative using GC-MS based verification analysis, we developed an LC-MS/MS-method for verification of hexahydrocannabinol (HHC) and Δ8-tetrahydrocannabinol. Assessment of HHC intake was based on identification of the following four metabolites: 11-nor-9(R)-carboxy-hexahydrocannabinol (R-HHC-COOH), 11-nor-9(S)-carboxy-hexahydrocannabinol (S-HHC-COOH), 11-hydroxy-9(R)-hexahydrocannabinol (R-HHC-OH) and 11-hydroxy-9(S)-hexahydrocannabinol (S-HHC-OH). Out of 46 urine samples analysed in this study, 44 showed presence of HHC-metabolites, which indicate HHC as the main explanation for an increased number of negative verifications for THC-COOH. In these samples, the HHC-OH metabolites occurred at a higher concentration than R-HHC-COOH while S-HHC-COOH was only detected in few samples at low concentrations. R-HHC-COOH and S-HHC-COOH can easily be added to a pre-existing verification method for THC-COOH, and still show acceptable results, while HHC-OH requires an enzyme capable of hydrolysing the ether glucuronide bond.

DNA Interaction and Cleavage Modes of Anthraquinone-Fused Enediynes: A Study on Tiancimycins, Yangpumicins, and Their Semisynthetic Analogues.

Dynemicin A has been the sole prototypical anthraquinone-fused enediyne (AFE) explored since its discovery in 1989. This study investigates the distinct DNA binding and cleavage mechanisms of emerging AFEs, represented by tiancimycins and yangpumicins, along with semisynthetic analogues. Our findings reveal their potent cytotoxicity against various tumor cell lines, while 18-methoxy tiancimycin A treatment could significantly suppress breast tumor growth with minimal toxicity. One of the most potent AFEs, i.e., tiancimycin A, preferentially targets DNA sequences 5'-ATT, 5'-CTT, 5'-GAA, 5'-GAT, and 5'-TTA. Molecular dynamics simulations suggest that emerging AFEs intercalate deeper into AT-rich DNA base pairs compared to dynemicin A. Importantly, tiancimycin A may equilibrate between insertional and intercalative modes without deintercalation, enabling selective cleavage of T and A bases. This study underscores how subtle structural variations among AFEs significantly influence their DNA recognition and cleavage, facilitating future design of novel AFEs as potent and selective payloads for antibody-drug conjugates.

Recent Advances in the Development of Polymyxin Antibiotics: 2010-2023.

The polymyxins are nonribosomal lipopeptides produced by Paenibacillus polymyxa and are potent antibiotics with activity specifically directed against Gram-negative bacteria. While the clinical use of polymyxins has historically been limited due to their toxicity, their use is on the rise given the lack of alternative treatment options for infections due to multidrug resistant Gram-negative pathogens. The Gram-negative specificity of the polymyxins is due to their ability to target lipid A, the membrane embedded LPS anchor that decorates the cell surface of Gram-negative bacteria. Notably, the mechanisms responsible for polymyxin toxicity, and in particular their nephrotoxicity, are only partially understood with most insights coming from studies carried out in the past decade. In parallel, many synthetic and semisynthetic polymyxin analogues have been developed in recent years in an attempt to mitigate the nephrotoxicity of the natural products. Despite these efforts, to date, no polymyxin analogues have gained clinical approval. This may soon change, however, as at the moment there are three novel polymyxin analogues in clinical trials. In this context, this review provides an update of the most recent insights with regard to the structure-activity relationships and nephrotoxicity of new polymyxin variants reported since 2010. We also discuss advances in the synthetic methods used to generate new polymyxin analogues, both via total synthesis and semisynthesis.

Synthesis and invitro antitumor activity of galactosamine-docetaxel conjugates.

Docetaxel (DTX) is a semi-synthetic analogue of paclitaxel which has attracted extensive attention in the treatment of cancer. However, the current clinically used DTX formulations display low tumor targeting ability, leading to unsatisfactory therapeutic outcomes with adverse effects, which poses significant challenges to the clinical application. In this study, three galactosamine (Gal) and docetaxel conjugates with different linkers were synthesized, namely DTX-(suc-Gal)2, DTX-(DTDPA-Gal)2, and DTX-(DSeDPA-Gal)2. These three conjugates were characterized by 1H NMR, FT-IR and HRMS. The invitro drug release study shows that DTX-(DTDPA-Gal)2 and DTX-(DSeDPA-Gal)2 exhibit glutathione (GSH)-responsive drug release and DTX-(DSeDPA-Gal)2 displays higher GSH-responsiveness. The invitro antitumor activity study shows that DTX-(DTDPA-Gal)2 and DTX-(DSeDPA-Gal)2 exhibit enhanced cytotoxicity, cell apoptosis rate and G2/M phase arrest against HepG2 cells as compared to DTX-(suc-Gal)2, DTX-(DSeDPA-Gal)2 displays the highest cytotoxicity, cell apoptosis rate and G2/M phase arrest among these three conjugates. In addition, DTX-(DSeDPA-Gal)2 exhibits higher selectivity to HepG2 cells as compared to free DTX. The DTX-(DSeDPA-Gal)2 developed in this study has been proven to be an effective DTX conjugate for selective killing hepatoma cells.

Chemical and Antiplasmodial Investigations on Eremophila-Derived Alkaloids and Semisynthetic Ether Analogues.

Microthecaline A (1), the known antiplasmodial quinoline serrulatane alkaloid from the roots of Eremophila microtheca F. Muell. ex Benth. (Scrophulariaceae), was targeted for isolation and subsequent use in the generation of a semisynthetic ether library. A large-scale extraction and isolation yielded the previously undescribed quinoline serrulatane microthecaline B (2), along with crystalline 1 that enabled the first X-ray crystallographic analysis to be undertaken on this rare alkaloid structure class. The X-ray diffraction analysis of 1 supported the absolute configuration assignment of microthecaline A, which was originally assigned by ECD data analysis. Microthecaline A (1) was converted into 10 new semisynthetic ether derivatives (3-12) using a diverse series of commercially available alkyl halides. Chemical structures of the new serrulatane alkaloid and semisynthetic ether analogues were assigned by spectroscopic and spectrometric analyses. Antiplasmodial evaluations of 1-12 showed that the semisynthetic derivative 5 elicited the most potent activity with an IC50 value of 7.2 μM against Plasmodium falciparum 3D7 (drug-sensitive) strain.

Anticancer Effect by Combined Treatment of Artemisia annua L. Polyphenols and Docetaxel in DU145 Prostate Cancer Cells and HCT116 Colorectal Cancer Cells.

Docetaxel (DTX), a semi-synthetic analogue of paclitaxel (taxol), is known to exert potent anticancer activity in various cancer cells by suppressing normal microtubule dynamics. In this study, we examined how the anticancer effect of DTX is regulated by polyphenols extracted from Korean Artemisia annua L. (pKAL) in DU145 prostate cancer cells (mutant p53) and HCT116 colorectal cancer cells (wild-type p53). Here, we show that the anticancer effect of DTX was enhanced more significantly by pKAL in HCT116 cells than in DU145 cells via phase-contrast microscopy, CCK-8 assay, Western blot, and flow cytometric analysis of annexin V/propidium iodide-stained cells. Notably, mutant p53 was slightly downregulated by single treatment of pKAL or DTX in DU145 cells, whereas wild-type p53 was significantly upregulated by pKAL or DTX in HCT116 cells. Moreover, the enhanced anticancer effect of DTX by pKAL in HCT116 cells was significantly associated with the suppression of DTX-induced p53 upregulation, increase of DTX-induced phospho-p38, and decrease of DTX-regulated cyclin A, cyclin B1, AKT, caspase-8, PARP1, GM130, NF-κB p65, and LDHA, leading to the increased apoptotic cell death and plasma membrane permeability. Our results suggest that pKAL could effectively improve the anticancer effect of DTX-containing chemotherapy used to treat various cancers expressing wild-type p53.

(370) Overview of Nonclinical Studies of LIB-01, a Novel Promising Oral Drug Under Development for Treatment of Erectile Dysfunction

Abstract Introduction LIB-01 is a novel molecule being developed as an oral drug for the treatment of erectile dysfunction (ED). It is a semi-synthetic analog, developed based on research on active compounds identified in root bark that had been used for treatment of male sexual disability since time immemorial. Objective In preparation for clinical development, a number of nonclinical studies on erectile function were conducted in normal and diabetic rats with ED. Studies to investigate the mechanism supporting the pro-erectile effect of LIB-01 were also conducted. A summary of the results from the nonclinical research program is presented. Methods Erectile response elicited by electrical stimulation of the cavernous nerve (ES CN) in anaesthetized rats was assessed. Intracavernous and arterial blood pressures were monitored according to a standardized experimental procedure. Mechanism of action studies were conducted with rat cavernosal tissue samples using immunohistochemistry and in ex vivo/organ chamber experiments. The isometric tension studies were conducted on cavernosal strips from LIB-01 treated and untreated Wistar rats. Cavernosal strips from untreated rats were incubated with either LIB-01 or DMSO (control) and then pre-contracted by phenylephrine (PHE). Concentration- or frequency response curves were performed on PHE pre-contracted strips in 3 consecutive steps: (i) cumulative addition of increasing acetylcholine (ACh) concentrations, (ii) electrical field stimulation (EFS) with increasing frequencies, and (iii), cumulative addition of increasing sodium nitroprusside (SNP) concentrations. Results A statistically significant pro-erectile facilitatory effect of LIB-01 has been repeatedly evidenced in all the studies conducted in anaesthetized control Wistar rats, by oral or subcutaneous administration of LIB-01 at 15 mg/kg/d, with an effect in the similar range as iv sildenafil 0.3mg/kg, when compared. The pro-erectile effect of LIB-01 was not acute, instead, the effect gradually increased and remained for at least 7 days post treatment. In addition, LIB-01 significantly improved erectile responses in anaesthetized diabetic Goto-Kakizaki ED rats compared to vehicle-treated rats, demonstrating the pro-erectile effect of LIB-01 in a robust validated pathophysiological rat model of type 2 diabetes. Immunohistochemistry experiments on cavernosal tissue from LIB-01 treated normal rats showed that neither CD31 nor nNOS expression was altered, thus likely ruling out any effect of LIB-01 on cavernosal micro-vascularization or cavernosal nNOS. Furthermore, only at a high concentration (10-5 M) was there a slight increase in the endothelium dependent relaxations induced by ACh compared to vehicle while LIB-01 did not exert any effect neither on endothelium-independent relaxations induced by SNP nor on nitrergic relaxation induced by EFS of untreated cavernosal strips exposed ex-vivo to different concentrations of LIB-01. Conclusions LIB-01 is a novel molecule which displays a significant pro-erectile effect in anesthetized normal rats as well as in diabetic rats with ED. The pro-erectile effect of LIB-01 is not acute, instead, the effect gradually increases and remains for at least 7 days post-treatment. Results from several mechanistic studies lead to postulate that the mechanism of LIB-01 does not recruit the NO-cGMP pathway thereby differing from phosphodiesterase type 5 inhibitors. A first-in-human clinical trial with LIB-01 is planned to start in 2023. Disclosure Yes, this is sponsored by industry/sponsor: Dicot AB. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Dicot AB.

Overview of the New Bioactive Heterocycles as Targeting Topoisomerase Inhibitors Useful Against Colon Cancer.

Colorectal cancer (CRC) is the third most common cancer globally, with high mortality. Metastatic CRC is incurable in most cases, and multiple drug therapy can increase patients' life expectancy by 2 to 3 years. Efforts are being made to understand the relationship between topoisomerase enzymes and colorectal cancer. Some studies have shown that higher expression of these enzymes is correlated to a poor prognosis for this type of cancer. One of the primary drugs used in the treatment of CRC is Irinotecan, which can be used in monotherapy or, more commonly, in therapeutic schemes such as FOLFIRI (Fluorouracil, Leucovorin, and Irinotecan) and CAPIRI (Capecitabine and Irinotecan). Like Camptothecin, Irinotecan and other compounds have a mechanism of action based on the formation of a ternary complex with topoisomerase I and DNA providing damage to it, therefore leading to cell death. Thus, this review focused on the principal works published in the last ten years that demonstrate a correlation between the inhibition of different isoforms of topoisomerase and in vitro cytotoxic activity against CRC by natural products, semisynthetic and synthetic compounds of pyridine, quinoline, acridine, imidazoles, indoles, and metal complexes. The results revealed that natural compounds, semisynthetic and synthetic derivatives showed potential in vitro cytotoxicity against several colon cancer cell lines, and this activity was often accompanied by the ability to inhibit both isoforms of topoisomerase (I and II), highlighting that these enzymes can be promising targets for the development of new chemotherapy against CRC. Pyridine analogs were considered the most promising for this study, while the evaluation of the real potential of natural products was limited by the lack of information in their work. Moreover, the complexes, although promising, presented as the main limitation the lack of selectivity.

Previously Uncharacterized Variants, OCF-E-OCF-J, of the Antifungal Occidiofungin Produced by Burkholderia contaminans MS14.

The rise of multidrug resistant fungal infections highlights the need to identify and develop novel antifungal agents. Occidiofungin is a nonribosomally synthesized glycolipopeptide that has a unique mechanism of action, disrupting actin-mediated functions and inducing cellular apoptosis. Antifungal activity has been observed in vitro against various fungal species, including multidrug resistant Candida auris, and in vivo efficacy has been demonstrated in a murine vulvovaginal candidiasis model. Occidiofungin, a cyclic glycolipopeptide, is composed of eight amino acids and in previous studies, an asparagine residue was assigned at position 7 (ASN7). In this study, new structural variants of occidiofungin have been characterized which have aspartic acid (ASP7), glutamine (GLN7), or glutamic acid (GLU7) at position 7. The side chain of the ASP7 variant contains the only terminal carboxylic acid in the peptide and provides a useful site for selective chemical modifications. Analogues were synthesized at the ASP7 position and tested for antifungal activity. These analogues were shown to be more active as compared to the ASP7 variant against a panel of Candida species. The naturally occurring variants of occidiofungin with a side chain containing a carboxylic acid at the seventh amino acid position can be used to develop semisynthetic analogues with enhanced therapeutic properties.