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Synthetic strategy toward ineleganolide: A cautionary tale.

ABSTRACT: We present a case study to demonstrate how complex molecule synthesis can benefit from quantum mechanics (QM) calculations. Theory is applied in two contexts: testing the chemical intuition used in retrosynthetic planning, along with expediting the resolution of unexpected challenges encountered during the course of the synthesis. From a computational lens, we examine retrospectively the strategies employed and the decisions made during our synthetic efforts toward the diterpenoid natural product ineleganolide. Seemingly logical and robust hypotheses are found to be ill-fated after theoretical investigation. Prior knowledge of these issues may have potentially saved valuable time and resources during our synthetic efforts. This cautionary tale suggests that synthetic campaigns can benefit from computational evaluation of synthetic plans.

SUBMITTER: Cusumano AQ

PROVIDER: S-EPMC8294177 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Synthetic strategy toward ineleganolide: A cautionary tale.

Cusumano Alexander Q AQ Houk K N KN Stoltz Brian M BM

Tetrahedron 20210623

We present a case study to demonstrate how complex molecule synthesis can benefit from quantum mechanics (QM) calculations. Theory is applied in two contexts: testing the chemical intuition used in retrosynthetic planning, along with expediting the resolution of unexpected challenges encountered during the course of the synthesis. From a computational lens, we examine retrospectively the strategies employed and the decisions made during our synthetic efforts toward the diterpenoid natural produc ...[more]

PMID: 34305185

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Project description:FURIN is a pro-protein convertase previously shown to be important for placental syncytialisation (Zhou et al. [1]), a process of cell fusion whereby placental cytotrophoblast cells fuse to form a multinucleated syncytium. This finding has been broadly accepted however, we have evidence suggesting the contrary. Spontaneously syncytialising term primary human trophoblast cells and BeWo choriocarcinoma cells were treated with either FURIN siRNA or negative control siRNA or the protease inhibitor, DEC-RVKR-CMK, or vehicle. Cells were then left to either spontaneously syncytialise (primary trophoblasts) or were induced to syncytialise with forskolin (BeWo). Effects on syncytialisation were measured by determining human chorionic gonadotrophin secretion and E-cadherin protein levels. We showed that FURIN is not important for syncytialisation in either cell type. However, in primary trophoblasts another protease also inhibited by DEC-RVKR-CMK, may be involved. Our results directly contrast with those published by Zhou et al. Zhou et al. however, used first trimester villous explants to study syncytialisation, and we used term primary trophoblasts. Therefore, we suggest that FURIN may be involved in syncytialisation of first trimester trophoblasts, but not term trophoblasts. What is more concerning is that our results using BeWo cells do not agree with their results, even though for the most part, we used the same experimental design. It is unclear why these experiments yielded different results, however we wanted to draw attention to simple differences in measuring syncytialisation or flaws in method reporting (including omission of cell line source and passage numbers, siRNA concentration and protein molecular weights) and choice of immunoblot loading controls, that could impact on experimental outcomes. Our study shows that careful reporting of methods by authors and thorough scrutiny by referees are vital. Furthermore, a universal benchmark for measuring syncytialisation is required so that various studies of syncytialisation can be validated.

Dataset Information

Synthetic strategy toward ineleganolide: A cautionary tale.

Publications

Synthetic strategy toward ineleganolide: A cautionary tale.

Similar Datasets

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