Chemical synthesis of 4'-thio and 4'-sulfinyl pyrimidine nucleoside analogues.

Mieke Guinan,Mark Smith,Chris S Hawes,Marcelo A Lima,Ningwu Huang,Gavin J Miller

doi:10.1039/d1ob02097h

Mieke Guinan, Mark Smith + Show 4 more

Open Access

https://doi.org/10.1039/d1ob02097h

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Abstract

Analogues of the canonical nucleosides required for nucleic acid synthesis have a longstanding presence and proven capability within antiviral and anticancer research. 4'-Thionucleosides, that incorporate bioisosteric replacement of furanose oxygen with sulfur, represent an important chemotype within this field. Established herein is synthetic capability towards a common 4-thioribose building block that enables access to thio-ribo and thio-arabino pyrimidine nucleosides, alongside their 4'-sulfinyl derivatives. In addition, this building block methodology is templated to deliver 4'-thio and 4'-sulfinyl analogues of the established anticancer drug gemcitabine. Cytotoxic capability of these new analogues is evaluated against human pancreatic cancer and human primary glioblastoma cell lines, with observed activities ranging from low μM to >200 μM; explanation for this reduced activity, compared to established nucleoside analogues, is yet unclear. Access to these chemotypes, with thiohemiaminal linkages, will enable a wider exploration of purine and triphosphate analogues and the application of such materials for potential resistance towards relevant hydrolytic enzymes within nucleic acid biochemistries.

Highlights

A significant proportion of current chemotherapeutic treatments for cancer involve the use of anti-metabolites, modified nucleoside analogues that possess a capability to mimic native purine or pyrimidine nucleosides, which can disrupt metabolic and regulatory pathways.[1]
Notwithstanding this significant medicinal capability, therapeutic intervention using nucleoside analogues is often limited by poor cellular uptake, low conversion to the active triphosphate metabolite, rapid degradation or clearance and development of resistance profiles in certain cell types.[2]
We have developed a scalable and column chromatography free synthesis of a protected 4-thioribose intermediate

Summary

Introduction

A significant proportion of current chemotherapeutic treatments for cancer involve the use of anti-metabolites, modified nucleoside analogues that possess a capability to mimic native purine or pyrimidine nucleosides, which can disrupt metabolic and regulatory pathways.[1]. Our synthesis of 4′-thio and 4′-sulfinyl nucleosides; we targeted an open-chain C1-oxime to enable sulfur inclusion using displacement of an appropriate 4-position leaving group, with concomitant ring closure onto a C1 aldehyde. This was intended to provide a benchmark in accessing related 2′deoxy-2′,2′-gem-difluoro and D-arabino structures which, alongside recent examples 2′-deoxy-2′-fluoro and L-3′-deoxy-3′,3′difluoro systems,[13,21,22] provides capability to more broadly study 4′-thionucleoside chemotypes and their structure activity relationships.

Results and discussion

Biological Evaluation

Conclusions