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A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol, bimatoprost, PGF_2α, fluprostenol, and travoprost guided by biocatalytic retrosynthesis.

ABSTRACT: Development of efficient and stereoselective synthesis of prostaglandins (PGs) is of utmost importance, owing to their valuable medicinal applications and unique chemical structures. We report here a unified synthesis of PGs cloprostenol, bimatoprost, PGF_2α, fluprostenol, and travoprost from the readily available dichloro-containing bicyclic ketone 6a guided by biocatalytic retrosynthesis, in 11-12 steps with 3.8-8.4% overall yields. An unprecedented Baeyer-Villiger monooxygenase (BVMO)-catalyzed stereoselective oxidation of 6a (99% ee), and a ketoreductase (KRED)-catalyzed diastereoselective reduction of enones 12 (87 : 13 to 99 : 1 dr) were utilized in combination for the first time to set the critical stereochemical configurations under mild conditions. Another key transformation was the copper(ii)-catalyzed regioselective p-phenylbenzoylation of the secondary alcohol of diol 10 (9.3 : 1 rr). This study not only provides an alternative route to the highly stereoselective synthesis of PGs, but also showcases the usefulness and great potential of biocatalysis in construction of complex molecules.

SUBMITTER: Zhu K

PROVIDER: S-EPMC8336452 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundProstaglandin F2α (PGF2α) is an important component for the physiology of female reproductive processes. In the literature, the data pertaining to the synthesis and action of PGF2α in early embryonic bovine development are limited. In our study, we used the bovine in vitro culture model based on the time of first cleavage to determine the mRNA expression and immunolocalization of PGF2α synthase and its receptor in bovine embryos from the 2-cell stage to the hatched blastocyst stage. We also evaluated PGF2α production at 2, 5 and 7 days of in vitro culture.ResultsWe found a significantly higher proportion of blastocysts obtained from the early-cleaved embryos than from the late-cleaved embryos (37.7% vs. 26.1% respectively, P < 0.05). The PGFS mRNA expression was significantly higher in the late-cleaved group than in the early-cleaved group at the 2-, 4- and 16-cell stages (P < 0.05). For PTGFR, we observed that within the late-cleaved group, the mRNA abundance was significantly higher in embryos at the 2- and 16-cell stages than in embryos at the 4- and 8-cell stages (P < 0.05). We observed that PTGFR mRNA expression was significantly higher in the 2- and 16-cell embryos in the late-cleaved group than that in the early-cleaved group embryos (P < 0.05). Among the blastocysts, the PGFS and PTGFR expression levels showed a trend towards higher mRNA expression in the late-cleaved group than in the early-cleaved group. Analysis of PGF2α production showed that within the early-cleaved group, the content of PGF2α in the in vitro culture medium was significantly higher on day 7 than it was on day 2 (P < 0.05).ConclusionsThe mRNA expression levels of PGF2α synthase and its receptor depend on the developmental stage and the embryo quality. Analyses of PGFS and PTGFR expression in bovine blastocysts and of PGF2α embryo production suggest that prostaglandin F2α can act in an autocrine and paracrine manner in bovine in vitro-produced preimplantation embryos. Moreover, the tendency of PTGFR and PGFS mRNA expression to be upregulated in embryos with low developmental potential can indicate a compensation mechanism related to high PGFS and PTGFR mRNA expression levels in low-quality embryos.

Project description:AimWithin the clinical setting, some patients have been identified as lacking in response to PGAs. This meta-analysis study aimed to evaluate the responsiveness of latanoprost, travoprost, bimatoprost, and tafluprost in OAG/OHT patients, latanoprost nonresponders (LNRs), and the IOP-reducing efficacy and safety.MethodsA literature search was conducted on PubMed, Embase, and the Cochrane Controlled Trials Register. The primary clinical endpoint was the number of responders at the end of the study. The secondary clinical endpoint was the IOP reduction at the endpoint from baseline. Safety evaluation included five common adverse events: conjunctival hyperemia, hypertrichosis, ocular burning, ocular itching, and foreign-body sensation.ResultsEleven articles containing ten RCTs were included in this meta-analysis study. The results highlighted that, in the OAG/OHT population, there was no statistically significant difference in the responsiveness of the four PGAs. Bimatoprost had a better IOP-reducing efficacy than latanoprost. There was no significant difference in the IOP-reducing efficacy of travoprost, latanoprost, and tafluprost. In LNRs, the responsiveness of bimatoprost, travoprost, and latanoprost did not show statistical differences. Bimatoprost reduced IOP with a greater extent than latanoprost and travoprost in LNRs, while there was no significant difference in the IOP-reducing efficacy of travoprost and latanoprost. No serious adverse events occurred with the treatment of the four PGAs. The prevalence of conjunctival hyperemia due to bimatoprost or tafluprost was significantly higher than that of latanoprost. Other adverse events had no significant difference between the four drugs.ConclusionThe existing studies cannot prove that latanoprost, travoprost, bimatoprost, and tafluprost have different responsiveness in OAG/OHT patients. Switching to bimatoprost or travoprost cannot achieve a significant improvement in responsiveness in LNRs. Bimatoprost has a better IOP-reducing efficacy than latanoprost and travoprost. No serious adverse events occurred during treatment with any medication we studied.

Project description:INTRODUCTION:The preservative benzalkonium chloride (BAK) is used to preserve several topical, intraocular pressure (IOP)-lowering glaucoma medications but can cause tolerability concerns that may lead to decreased adherence to treatment and ultimately diminish the effectiveness of IOP control. The study aimed to determine the efficacy and tolerability of BAK-free travoprost preserved with polyquaternium-1 in glaucoma patients switched from BAK-preserved latanoprost or bimatoprost. METHODS:This 12-week, open-label study was conducted in Europe between December 2011 and February 2013. We enrolled adult patients with open-angle glaucoma or ocular hypertension who were receiving BAK-preserved latanoprost 0.005% or bimatoprost 0.01% and, in the opinion of the investigator, would benefit from transition to BAK-free travoprost 0.004% preserved with polyquaternium-1 because of tolerability concerns. Assessments included IOP, proportion of patients with IOP ?18 mmHg, ocular surface status, hyperemia, patient treatment preference, and adherence. Adverse events were recorded throughout the study. RESULTS:Of the 202 patients screened, 187 patients were included in the intent-to-treat population (mean age, 66.6 years; range, 19-90 years). The mean IOP significantly reduced from baseline (17.0 mmHg) to week 6 (mean change, -1.17 mmHg; P<0.001) and week 12 (-1.16 mmHg; P<0.001). At week 12, more patients achieved IOP ?18 mmHg (81.2% versus 73.3% at baseline), and ocular surface disease severity improved from baseline to week 12. Most patients preferred BAK-free travoprost (74.9%) versus their previous medication and were very confident in their adherence (84.1%). Reduced visual acuity and eye pruritus were the most common adverse events (2.5% each). CONCLUSION:BAK-free travoprost 0.004% preserved with polyquaternium-1 was efficacious and well tolerated and may be an advantageous prostaglandin analog option for patients with open-angle glaucoma or ocular hypertension who are intolerant to BAK-preserved latanoprost or bimatoprost.

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A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol, bimatoprost, PGF_2α, fluprostenol, and travoprost guided by biocatalytic retrosynthesis.

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A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost guided by biocatalytic retrosynthesis.

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OmicsDI is part of the ELIXIR infrastructure

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A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol, bimatoprost, PGF_2α, fluprostenol, and travoprost guided by biocatalytic retrosynthesis.