Acid Analogues Research Articles

Engineering the catechol 1,2-dioxygenase from Arthrobacter sp. with improved activity toward 4-alkyl substituted catechols

Catechol 1,2-dioxygenase (CAT) is a key enzyme in the cis, cis-muconic acid biosynthesis pathways. However, CAT demonstrates limited catalytic ability to the substrate 4-alkyl substituted catechols, and its application in biocatalysis remains underexplored. Here, a CAT from Arthrobacter sp. CGMCC 3584 (ArCAT) was overexpressed in Escherichia coli for the first time. Subsequently, the structure-guided semi-rational engineering of ArCAT was employed to generate small and precise mutation libraries, and the mutant I206V exhibited the best catalytic ability. Molecular docking analysis revealed that the mutant I206V provided additional hydrophobic interactions and hydrogen bonds with the substrates in the catalytic activity pocket compared with the wild type (WT) for both 4-ethylcatechol and 4-n-propylcatechol. Furthermore, binding free energy calculations showed that the mutant I206V had a better binding affinity to 4-ethylcatechol or to 4-n-propylcatechol compared to the WT, in good agreement with the results of kinetic parameters. Finally, in small-scale biotransformation based on crude enzymes, the mutant I206V enhanced the overall conversion rates of 4-ethylcatechol and 4-n-propylcatechol by 15.28 % and 25.55 %, respectively, compared to the WT. This study presented a smart strategy for improving ArCAT activity, and revealed the potential application of ArCAT in biological production of muconic acid analogs from branched catechols.

Dehydroabietylamine exerts antitumor effects by affecting nucleotide metabolism in gastric cancer.

Nucleotide metabolism is the ultimate and most critical link in the self-replication process of tumors, including gastric cancer (GC). However, in clinical treatment, classic antitumor drugs such as 5-fluorouracil (5-FU) are mostly metabolic analogs of purines or pyrimidines, which lack specificity for tumor cells and therefore have significant side effects. It is unclear whether there are other drugs that can target nucleotide metabolism, except for nucleic acid analogs. Here, we found that a natural compound, dehydroabietylamine (DHAA), significantly reduced the viability and proliferation of GC cells and organoids. DHAA disrupts the purine and pyrimidine metabolism of GC cells, causing DNA damage and further inducing apoptosis. DHAA treatment decreased transcription and protein levels of key enzymes involved in the nucleotide metabolism pathway, with significant reductions in the expression of pyrimidine metabolism key enzymes CAD, DHODH, and purine metabolism key enzymes PAICS. We also found that DHAA directly binds to and reduces the expression of Forkhead box K2 (FOXK2), a common transcription factor for these metabolic enzymes. Ultimately, DHAA was shown to delay tumorigenesis in K19-Wnt1/C2mE transgenic mice model and reduce levels of CAD, DHODH, and PAICS in vivo. We demonstrate that DHAA exerts an anticancer effect on GC by targeting transcription factor FOXK2, reducing transcription of key genes for nucleotide metabolism and impairing nucleotide biosynthesis, thus DHAA is a promising candidate for GC therapy.

Synthesis of Seven-Membered Ring Nucleosides and Serendipitous Simmons-Smith O-Glycosylation.

A series of seven-membered (oxepine) nucleosides containing various nucleobases (A, U, T, 5-FU, C) were synthesized by ring expansion of cyclopropanated glucals. We expect this new series of ring-expanded nucleic acid analogues to be useful as building blocks in the design of mixed base functional genetic systems. While exploring alternative pathways to oxepine nucleoside synthesis, we discovered an unprecedented α-stereoselective O-glycosylation of 1,2-glucals under mild Simmons-Smith conditions.

Targeted Photodynamic Therapy using a Vectorized Photosensitizer coupled to Folic Acid Analog induces Ovarian Tumor Cell Death and inhibits IL-6-mediated Inflammation

Ovarian cancer (OC) is one of the most lethal cancers among women. Frequent recurrence in the peritoneum due to the presence of microscopic tumor residues justifies the development of new therapies. Indeed, our main objective is to develop a targeted photodynamic therapy (PDT) treatment of peritoneal carcinomatosis from OC to improve the life expectancy of cancer patients. Herein, we propose a targeted-PDT using a vectorized photosensitizer (PS) coupled with a newly folic acid analog (FAA), named PSFAA, in order to target folate receptor alpha (FRα) overexpressed on peritoneal metastasis.This PSFAA was the result of the coupling of pyropheophorbide-a (Pyro-a), as the PS, to a newly synthesized FAA via a polyethylene glycol (PEG) spacer. The selectivity and the PDT efficacy of PSFAA was evaluated on two human OC cell lines overexpressing FRα compared to fibrosarcoma cells underexpressing FRα.Final PSFAA, including the synthesis of a newly FAA and its conjugation to Pyro-a, was obtained after 10 synthesis steps, with an overall yield of 19%. Photophysical properties of PSFAA in EtOH were performed and showed similarity with those of free Pyro-a, such as the fluorescence and singlet oxygen quantum yields (Φf = 0.39 and ΦΔ = 0.53 for free Pyro-a, and Φf = 0.26 and ΦΔ = 0.41 for PSFAA). Any toxicity of PSFAA was noticed. After light illumination, a dose-dependent effect on PS concentration and light dose was shown. Furthermore, a PDT efficacy of PSFAA on OC cell secretome was detected inducing a decrease of a pro-inflammatory cytokine secretion (IL-6).This new PSFAA has shown promising biological properties highlighting the selectivity of the therapy opening new perspectives in the treatment of a cancer in a therapeutic impasse.

Surufatinib combined with TAS-102 in third- or later-line therapy of patients with metastatic pancreatic cancer (mPDAC): An open-label, single-arm, phase II study.

e16297 Background: Patients (pts) with mPDAC refractory to FOLFIRINOX and AG have limited therapeutic options. TAS-102 is an orally administered combination of a thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride, and may have activity in 5-FU resistant malignancies. Overexpression of VEGF has been reported in pancreatic cancer and anti-angiogenesis regimens have shown clinical benefits in mPDAC. Surufatinib is a potent, small-molecule tyrosine kinase inhibitor (TKI), selectively targeting VEGFR 1, 2, and 3, FGFR 1, and CSF-1R. This study aimed to assess the efficacy and safety of orally surufatinib combined with TAS-102 in third- or later-line mPDAC. Here we report the preliminary results. Methods: This tiral enrolled pts with histologically confirmed PDAC, ECOG PS 0-1, at least one measurable lesion and have received ≥2 prior chemotherapy regimens in an advanced setting. Pts were treated with surufatinib (250mg once daily) and TAS-102 (35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From 01/2023 to 12/2023, 17 pts were enrolled (median age 60, 58.8% male). All pts have an ECOG PS 1 and 88.2% had more than 3 sites of metastases. The most common metastatic sites were peritoneum (64.7%), liver (52.9%) and lymph nodes (52.9%), 52.9% of pts had ≥3L prior therapy and 64.7% with primary site on pancreatic body and tail. At the cutoff data on December 20, 2023, one patient continued to receive surufatinib and TAS-102, 11 pts were included in the efficacy analysis. The ORR was 27.3% (95% CI: 6.0-61.0%), with 3 pts achieved partial response (PR). SD was 1(9.1%) with a DCR of 36.4% (4/11) (95% CI: 10.9-69.2%). The median PFS was 3.19 mo (95%CI 1.91-3.94) and PFS rate at 3 months (PFSR3mon) was 54.5%. Among the 8 pts without liver metastases, the ORR was 37.5% (3/8) (95% CI: 8.5-75.5%) and the DCR was 50.0% (4/8) (95% CI: 15.7-84.3%), the median PFS was 3.56 mo (95%CI 2.14-NA) and PFSR3mon was 62.5%. All 17 pts experienced treatment-related AEs (TRAEs), with the most common AEs of all grades were hematological including leukopenia (47.1%), neutropenia (41.2%), lymphopenia (41.2%), bilirubin increased (35.3%) and hypoalbuminemia (29.4%). Grades ≥ 3 were neutropenia (23.5%), lymphopenia (17.6%) and anemia (11.8%). Conclusions: Surufatinib combined with TAS-102 in third- or later-line mPDAC showed encouraging anti-tumor activity and acceptable safety profile, especially in pts without liver metastasis. This trial is ongoing and further molecular biomarkers exploration are warranted. Clinical trial information: NCT05481463 .

Hybrid Caffeic Acid-Based DHFR Inhibitors as Novel Antimicrobial and Anticancer Agents.

A novel series of 1,2,4-triazole analogues of caffeic acid was designed, synthesized, characterized, and assessed for their capacity to inhibit DHFR, as well as their anticancer and antimicrobial properties. A molecular docking analysis was conducted on DHFR, utilizing PDB IDs 1U72 and 2W9S, aiming to design anticancer and antimicrobial drugs, respectively. Among all the synthesized derivatives, compound CTh7 demonstrated the highest potency as a DHFR inhibitor, with an IC50 value of 0.15 μM. Additionally, it exhibited significant cytotoxic properties, with an IC50 value of 8.53 µM. The molecular docking analysis of the CTh7 compound revealed that it forms strong interactions with key residues of homo sapiens DHFR such as Glu30, Phe34, Tyr121, Ile16, Val115, and Phe31 within the target protein binding site and displayed excellent docking scores and binding energy (-9.9; -70.38 kcal/mol). Additionally, synthesized compounds were screened for antimicrobial properties, revealing significant antimicrobial potential against bacterial strains and moderate effects against fungal strains. Specifically, compound CTh3 exhibited notable antibacterial efficacy against Staphylococcus aureus (MIC = 5 µM). Similarly, compound CTh4 demonstrated significant antibacterial activity against both Escherichia coli and Pseudomonas aeruginosa, with MIC values of 5 µM for each. A docking analysis of the most active antimicrobial compound CTh3 revealed that it forms hydrogen bonds with Thr121 and Asn18, a π-cation bond with Phe92, and a salt bridge with the polar residue Asp27.

#1505 Late-onset lupus nephritis: clinical-epidemiological, histological, prognostic and therapeutical implications: a single center experience

Abstract Background and Aims Systemic lupus erythematosus (SLE), a chronic autoimmune disease, and lupus nephritis (LN), are typically diagnosed in women in fertile age. Late-onset SLE is defined as a disease onset over 50 years. Our main objective was to analyze the clinical, histological, prognostic and therapeutical features related to LN in our late-onset SLE population. Method A single center and retrospective study was performed comparing clinical-demographic, histological, prognostic and therapeutical data of 45 LN biopsied patients from 1994 to 2023. We divided the study population according to the age of onset of LN into classic-onset (< 45 years) and late-onset (> 45 years). Results Late-onset LN patients showed a higher association with Sjögren's and antiphospholipid syndrome, more cardiovascular comorbidities at presentation, poorer renal function at diagnosis and higher SDI score. On histology they showed more non-proliferative LN classes (II followed by V). Late-onset LN responders needed more time to achieve response but had fewer relapses. Non responsive patients had more incidence of acute kidney injury (AKI) and more glomerulosclerosis and interstitial fibrosis-tubular atrophy (IFTA) at presentation, as well as more need for renal replacement therapy (RRT) at diagnosis and at follow-up. The principal independent variables associated with relapse were the younger age at SLE diagnosis and an initial partial renal response (PRR). Patients of both groups who experienced relapse received higher doses of intravenous cyclophosphamide and less mycophenolic acid (MFA) analogues. Patients who received induction with MFA analogues were more likely to achieve complete renal response (CRR) or non-renal response (NRR). Conclusion late-onset LN is often accompanied by poor renal function at presentation. It seems imperative to establish a tailored approach in this fragile population in order to avoid unnecessary immunosuppression.

#289 Lipocalin-2 promotes cardiovascular calcification in chronic kidney disease by upregulating STAT3/NCOA4-mediated ferritinophagy and ferroptosis

Abstract Background and Aims Cardiovascular calcification (CVC) is a common complication of chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality without any effective therapies. To date, the underlying mechanism of CKD-CVC has not been elucidated. Recent studies suggest that ferroptosis is a novel programmed cell death that may play a role in the process of CKD-CVC, but the mechanism is largely unclear. Ferritinophagy is an important inducer of ferroptosis that is regulated by nuclear receptor coactivator 4 (NCOA4). However, the relationship between ferritinophagy and CKD-CVC has not been explored. Lipocalin-2 (LCN2) is an iron-trafficking protein that has been associated with both osteogenesis and ferroptosis, but the exact role and molecular mechanism of LCN2 in CKD-CVC needs to be explored. Method A cross-sectional clinical study was utilized to examine the association between LCN2 expression and CKD-CVC in serum and calcified radial arteries of CKD patients. LCN2 knockout mice, their wild type littermates and mice infected with VSMCs-targeted adeno-associated virus encoding LCN2 gene or negative control gene were all fed by the high adenine and phosphate diet to induce CKD-CVC.VSMCs transfected with LCN2-overexpressing lentivirus, LCN2-shRNA lentivirus or LCN2 siRNA and recombinant LCN2 stimulated VSMCs were treated under the condition of calcifying medium to investigate the role of LCN2 in CKD-CVC in vitro. Cardiovascular calcification was evaluated by Von-kossa staining and tissue calcium content assay. VSMCs calcification were checked by the Alizarin Red Staining and cellular calcium content assay. Cellular reactive oxygen species (ROS) were measured by the DCFDA assay. Lipid peroxidation was measured by the fluorescence of the fatty acid analog C11-BODIPY581/591 probe. Intracellular labile ferrous iron levels were measured by fluorescence of Phen Green SK probe and ferro-orange probe. Transmission electron microscopy was also used to examine mitochondrial change of ferroptosis. Results The cross-sectional study identified that LCN2 levels in serum and radial arteries were significantly increased as the severity of CKD-CVC increased. High adenine and phosphate diet intake provokes renal fibrosis and cardiovascular calcification in vivo. In vitro, five-days high phosphate sodium stimulation induced calcium deposition and osteoblastic trans differentiation of VSMCs. Meanwhile, high phosphate also increased the levels of ferroptosis in VSMCs as evidenced by decreased cell viability, iron and ROS accumulation, upregulated PTGS2 and MDA levels, reduced glutathione peroxidase 4 (GPX4) levels and significantly mitochondrial damage in VSMCs. Intriguingly, calcium deposition in VSMCs could be reversed by the ferroptosis inhibitor ferrostatin-1. LCN2 expression was significantly upregulated both in the aorta of mice and calcified VSMCs. Compared with WT mice, deletion of LCN2 inhibited cardiovascular calcification whereas VSMC-targeted LCN2 overexpression aggravated CKD-CVC. Consistently, LCN2 knockdown also alleviated calcium deposition of VSMCs. Meanwhile, inhibition of ferroptosis were observed after LCN2 silencing as evidenced by decreased ferrous and lipid oxidation while increased levels of GPX4. Mechanically, we demonstrated high phosphate increased the protein level of NCOA4 and downregulated FTH1, which was reversed by depletion of LCN2. Knockdown of NCOA4 partly alleviated the ferritin reduction, ferroptosis, and calcification in VSMCs, indicating that NCOA4-mediated ferritinophagy was required for VSMCs calcification. Furthermore, we found that the recombinant LCN2 treatment significantly upregulated phosphorylated STAT3. STAT3 signaling inhibitor abolished the recombinant LCN2 induced NCOA4 upregulation and calcification in VSMCs. Conclusion Our findings indicate that the pro-calcific effect of high phosphate is due to VSMCs ferroptosis mediated by LCN2 upregulation. LCN2 silencing alleviates CKD-CVC by suppressing the STAT3/ NCOA4/FTH1 signaling mediated ferritinophagy. LCN2 could serve as a candidate therapeutic strategy for CKD-CVC.

Selective adsorption and separation of salicylic acid and 4‐hydroxyisophthalic acid from industry‐grade 4‐hydroxybenzoic acid on UiO‐66

AbstractIn this study, UiO‐66 was employed for the first time as an adsorbent to separate phenolic acid analogues, specifically 4‐hydroxyisophthalic acid and salicylic acid, from impurities. Synthesized in‐house, UiO‐66 was shown to exhibit high selectivity towards 4‐HIPA/4‐HBA and SA/4‐HBA when a molar equivalent of acetic acid modulator to terephthalic acid was set at 44. The adsorption capacities for 4‐HBA, 4‐HIPA, and SA were determined to be 56.34, 55.02, and 60.34 mg/g, respectively. Furthermore, it was observed that after six regeneration cycles, the adsorption capacity for 4‐HBA remained nearly unchanged, whereas those for 4‐HIPA and SA decreased by 5.6% and 2.6%, respectively. FTIR and XPS analyses revealed that all three compounds were adsorbed at the same dominant Zr cluster site on UiO‐66, primarily through hydrogen bonding and electrostatic interaction. Dynamic adsorption experiments revealed that 4‐HBA was the first to elute, maintaining the residual contents of 4‐HIPA and SA below 0.1 wt%. Compared to traditional separation techniques, this paper provided a simple and effective method to purify industrial grade 4‐hydroxybenzoic acid.

Establishment of human induced pluripotent stem cell-derived hepatobiliary organoid with bile duct for pharmaceutical research use

In vitro models of the human liver are promising alternatives to animal tests for drug development. Currently, primary human hepatocytes (PHHs) are preferred for pharmacokinetic and cytotoxicity tests. However, they are unable to recapitulate the flow of bile in hepatobiliary clearance owing to the lack of bile ducts, leading to the limitation of bile analysis. To address the issue, a liver organoid culture system that has a functional bile duct network is desired. In this study, we aimed to generate human iPSC-derived hepatobiliary organoids (hHBOs) consisting of hepatocytes and bile ducts. The two-step differentiation process under 2D and semi-3D culture conditions promoted the maturation of hHBOs on culture plates, in which hepatocyte clusters were covered with monolayered biliary tubes. We demonstrated that the hHBOs reproduced the flow of bile containing a fluorescent bile acid analog or medicinal drugs from hepatocytes into bile ducts via bile canaliculi. Furthermore, the hHBOs exhibited pathophysiological responses to troglitazone, such as cholestasis and cytotoxicity. Because the hHBOs can recapitulate the function of bile ducts in hepatobiliary clearance, they are suitable as a liver disease model and would be a novel in vitro platform system for pharmaceutical research use.

Experimental and computational studies of novel amide analogues of ferulic acid as potential MDM2 inhibitors to retrieve p53 function

Phytochemicals are naturally occurring substances that possess heightened levels of antioxidants. Among these, ferulic acid (FA) is widely found in fruits and vegetables, including sweet corn, tomatoes, rice bran, and is recognized for its antioxidant qualities. Various diseases include cancer, cardiomyopathy, skin, brain disorders, viral infections and diabetes are the oxidative stress-based diseases could benefit from FA's treatment. However, ferulic acid's antioxidant properties were lowered by its hydophobicity, which prevents it from autoxidation of fats and oils. However, its physicochemical and pharmacological properties can be improved by the addition of amide groups which is highly desirable. In the present investigation, two new amide analogues of ferulic acid, FA2 and FA3, were designed, synthesized and screened to assess the potential of these compounds in computational and invitro experiments. Ferulic acid analogues were biologically evaluated on K562 cells, and the results revealed that FA3, a synthesized analogue of ferulic acid, demonstrated a greater degree of inhibition that FA2 as well as the original molecule of ferulic acid, suggesting its strong antioxidant activity. Utilizing MDM2 as a receptor, we carried out docking and dynamic studies to gain an understanding of the potential molecular mechanism by which the action was carried out. The docking and dynamic results showed that FA3 has showed higher rates binding energy -6.04 Kcal/Mol than FA2 -4.55 04 Kcal/Mol, and ferulic acid -4.19 Kcal/Mol. All the molecules are interacted with the residues involved in p53 binding of MDM2 protein. This study clearly revealed that FA3 ferulic acid analogue interacts with MDM2 amino acids that might have inhibited by the binding of MDM2 to p53.

Cobalt‐Catalyzed Enantioselective Reductive α‐Chloro‐Carbonyl Addition of Ketimine to Construct the β‐Tertiary Amino Acid Analogues

Abstractβ‐Tertiary amino acid derivatives constitute one of the most frequently occurring units in natural products and bioactive molecules. However, the efficient asymmetric synthesis of this motif still remains a significant challenge. Herein, we disclose a cobalt‐catalyzed enantioselective reductive addition reaction of ketimine using α‐chloro carbonyl compound as a radical precursor, providing expedient access to a diverse array of enantioenriched β‐quaternary amino acid analogues. This protocol exhibits outstanding enantioselectivity and broad substrate scope with excellent functional group tolerance. Preliminary mechanism studies rule out the possibility of Reformatsky‐type addition and confirm the involvement of radical species in stereoselective addition process. The synthetic utility has been demonstrated through the rapid assembly of iterative amino acid units and oligopeptide, showcasing its versatile platform for late‐stage modification of drug candidates.

Cobalt-Catalyzed Enantioselective Reductive α-Chloro-Carbonyl Addition of Ketimine to Construct the β-Tertiary Amino Acid Analogues.

β-Tertiary amino acid derivatives constitute one of the most frequently occurring units in natural products and bioactive molecules. However, the efficient asymmetric synthesis of this motif still remains a significant challenge. Herein, we disclose a cobalt-catalyzed enantioselective reductive addition reaction of ketimine using α-chloro carbonyl compound as a radical precursor, providing expedient access to a diverse array of enantioenriched β-quaternary amino acid analogues. This protocol exhibits outstanding enantioselectivity and broad substrate scope with excellent functional group tolerance. Preliminary mechanism studies rule out the possibility of Reformatsky-type addition and confirm the involvement of radical species in stereoselective addition process. The synthetic utility has been demonstrated through the rapid assembly of iterative amino acid units and oligopeptide, showcasing its versatile platform for late-stage modification of drug candidates.

Long-term oral administration of Kelisha capsule does not cause hepatorenal toxicity in rats

Ethnopharmacological relevanceKelisha capsules (KLS) are often used to treat acute diarrhoea, bacillary dysentery, heat stroke, and other diseases. One of its components, Asarum, contains aristolochic acid I which is both nephrotoxic and carcinogenic. However, the aristolochic acid (AA) content in KLS and its toxicity remain unclear. Aim of the studyThe aims of this study were to quantitatively determine the contents of five aristolochic acid analogues (AAAs) in Asarum and KLS, and systematically evaluate the in vivo toxicity of KLS in rats. Materials and methodsUltra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the content of the five AAAs in Asarum and KLS. Sprague–Dawley rats were administered KLS at 0, 0.75, 1.5, and 3.0 g/kg respectively, and then sacrificed after 4 weeks of administration or after an additional 2 weeks of recovery. The endpoints assessed included body weight measurements, serum biochemistry and haematology indices, and clinical and histopathological observations. ResultsThe AAAs content in Asarum sieboldii Miq. (HB-ESBJ) were much lower than those of the other Asarums. The contents of AA I, AA IVa, and aristolactam I in KLS were in the ranges of 0.03–0.06 μg/g, 1.89–2.16 μg/g, and 0.55–1.60 μg/g, respectively, whereas AA II and AA IIIa were not detected. None of the rats showed symptoms of toxic reactions and KLS was well tolerated throughout the study. Compared to the control group, the activated partial thromboplastin time values of rats in the 1.5 and 3.0 g/kg groups significantly reduced after administration (P < 0.05). In addition, the serum triglycerides of male rats in the 0.75 and 1.5 g/kg groups after administration, and the 0.75, 1.5, 3.0 g/kg groups after recovery were significantly decreased (P < 0.01 or P < 0.001). No significant drug-related toxicological changes were observed in other serum biochemical indices, haematology, or histopathology. ConclusionsThe AA I content in KLS met the limit requirements (<0.001%) of the Chinese Pharmacopoeia. Therefore, it is safe to use KLS in the short-term. However, for safety considerations, attention should be paid to the effects of long-term KLS administration on coagulation function and triglyceride metabolism.

Amino acid analogues provide multiple plausible pathways to prebiotic peptides.

Prebiotic peptide synthesis has consistently been a prominent topic within the field of the origin of life. While research predominantly centres on the 20 classical amino acids, the synthesis process encounters significant thermodynamic barriers. Consequently, amino acid analogues are being explored as potential building blocks for prebiotic peptide synthesis. This review delves into the pathway of polypeptide formation, identifying specific amino acid analogues that might have existed on early Earth, potentially participating in peptide synthesis and chemical evolution. Moreover, considering the complexity and variability of the environment on early Earth, we propose the plausibility of coevolution between amino acids and their analogues.

Molecular docking of ferulic acid analogue compounds against epidermal growth factor receptor as a potential therapy for breast cancer

Background: Triple-negative breast cancer (TNBC) accounted for 18.1% of the breast cancer cases that occurred in Indonesia until 2020. Epidermal growth factor receptor (EGFR) overexpression is found in at least 50% of TNBC cases. So far, it is necessary to find an anti-cancer compound that has the potential against TNBC-type breast cancer to achieve good health and well-being. Objective: Ferulic acid derivatives were designed to be active on EGFR in silico study. Methods: Molecular docking was performed using Auto Dock 1.5.7 and PyRx 0.8 software, and visualisation was observed using Discovery Studio. FA ligand and its four derivatives were docked into the receptor EGFR (PDB ID: 3W33). Results: It was found that ferulic acid derivatives have high potential as an anticancer through EGFR inhibition in TNBC-type breast cancer. 4-(4-methyl) benzoyloxy-3-methoxycinnamic acid had the best potential among other derivatives, which showed the lowest binding free energy of -8.81 kcal/mol and the smallest Ki of 352.65nM. Methyl substitution at the benzoyloxy increased ligand interaction with amino acids in EGFR by increasing hydrophobic π-alkyl, π-π and alkyl binding with amino acids. Conclusion: The 4-(4-methyl) benzoyloxy-3-methoxycinnamic acid was the most prospective compound as an EGFR inhibitor and predicted as the most potential compound against breast cancer.

Synthesis and enzymatic resolution of novel analogs of alicyclic and heterocyclic mandelic acid derivatives

Synthesis and enzymatic resolution of a new class of alicyclic and heterocyclic mandelic acid derivatives was described. The method relied on the preparation of cyanohydrins from the commercially available aldehydes followed by hydrolysis to corresponding racemic hydroxy esters that were used in the resolution with the Amano PS enzyme. An alternative approach was proposed for compounds that were not suitable for this procedure. For the selected examples, synthesis of the corresponding mandelic acid analogs using the subsequent hydrolysis of esters followed by enantiomeric enrichment via recrystallization of the diastereomeric salt was performed.

Effect of Nucleic Acid Analog Administration on Fluctuations in the Albumin-to-Globulin Ratio in Cats with Feline Infectious Peritonitis.

feline infectious peritonitis (FIP) is a fatal disease in cats classified as either effusive ('wet'), non-effusive ('dry'), or a mixture of both forms ('mixed'). The anti-FIP therapeutic effects of Mutian and molnupiravir, two drugs with a nucleic acid analog as an active ingredient, have been confirmed recently. Of the cats with FIP, we observed a total of 122 and 56 cases that achieved remission after the administration of Mutian and molnupiravir as routine treatments, respectively. Changes in clinical indicators suggested to be correlated with FIP remission (weight, hematocrit, and albumin-to-globulin ratio) before and after the administration of each drug and during follow-up observation were statistically compared for each FIP type. In all three FIP types, the administration of either Mutian or molnupiravir resulted in statistically significant increases in these indicators. Furthermore, the effect of Mutian on improving the albumin-to-globulin ratio was not observed at all in wet FIP, as compared with that of molnupiravir, but statistically significant in mixed and dry (p < 0.02 and p < 0.003, respectively). The differences in albumin-to-globulin ratio were all due to those of circulating globulin levels. These results indicate that slight inflammatory responses might be elicited continuously by a residual virus that persisted through molnupiravir treatments.

Evaluation of Pyrazinamide and Pyrazinoic Acid Analogues for Control of Key Weeds in Multiple Crops

Evaluation of Pyrazinamide and Pyrazinoic Acid Analogues for Control of Key Weeds in Multiple Crops

Appropriate use of medication among home care adult cancer patients at end of life: a retrospective observational study

BackgroundMedications are commonly used for symptom control in cancer patients at the end of life. This study aimed to evaluate medication utilization among home care palliative patients with cancer at the end of life and assess the appropriateness of these medications.MethodThis retrospective observational study included adult cancer patients who received home care in 2020. Medications taken during the last month of the patient’s life were reviewed and classified into three major categories: potentially avoidable, defined as medications that usually have no place at the end of life because the time to benefit is shorter than life expectancy; medications of uncertain appropriateness, defined as medications that need case-by-case evaluation because they could have a role at the end of life; and potentially appropriate, defined as medications that provide symptomatic relief.ResultsIn our study, we enrolled 353 patients, and 2707 medications were analyzed for appropriateness. Among those, 1712 (63.2%) were classified as potentially appropriate, 755 (27.9%) as potentially avoidable, and 240 (8.9%) as medications with uncertain appropriateness. The most common potentially avoidable medications were medications for peptic ulcers and gastroesophageal reflux disease (30.5%), vitamins (14.6%), beta-blockers (9.8%), anticoagulants (7.9%), oral antidiabetics (5.4%) and insulin products (5.3%). Among the potentially appropriate medications, opioid analgesics were the most frequently utilized medications (19.5%), followed by laxatives (19%), nonopioid analgesics (14.4%), gamma-aminobutyric acid analog analgesics (7.7%) and systemic corticosteroids (6%).ConclusionIn home care cancer patients, approximately one-third of prescribed medications were considered potentially avoidable. Future measures to optimize medication use in this patient population are essential.