Synthesis, Anti‐HIV Activity Studies, and in silico Rationalization of Cyclobutane‐Fused Nucleosides

Abstract

The present work describes some recent approaches to novel 3-oxabicyclo[3.2.0]heptane-type nucleosides structurally similar to the potent anti-HIV agent stavudine (d4T). To gain knowledge at the molecular level relevant for further synthetic designs, the lack of activity of these compounds was investigated by computational approaches accounting for three main physiological requirements of anti-HIV nucleosides: their drug-likeness, their activation process, and their subsequent interaction with HIV reverse transcriptase (HIV-RT). Our results show that the inclusion of the fused cyclobutane at the 2'- and 3'-positions of the sugar portion provides drug-like compounds. Nonetheless, the presence of this cyclobutane moiety prevents binding orientations consistent with the catalytic activation for at least one of the enzymes known to activate d4T. To the best of our knowledge, this is the first study to explicitly consider the simulation of the entire activation process to rationalize anti-HIV activities.

The switch-off method: rapid investigation of flow photochemical reactions

“…[2 + 2] photocycloaddition of alkene and alkyne [2 + 2] photocycloadditions are an important set of reactions forming cyclobutene compounds using relatively mild conditions 23,24 which can then be used as synthetic intermediates to form many different compounds, [25][26][27] natural products, 28,29 and biologically active molecules [30][31][32] containing the cyclobutene motif. Additionally, [2 + 2] photocycloadditions have been performed under continuous flow conditions by several groups [33][34][35][36][37] demonstrating the reactions suitability towards study via the switch-off methodology.…”

Conformational Restriction: An Effective Tactic in ‘Follow-On’-Based Drug Discovery

“…With aim to seek novel nucleosides endowed with potent bioactivities, conformationally restricted modifications of the sugar moieties in natural nucleosides have been performed [52], which resulted in the synthesis of hexahydroisobenzofuran nucleoside 49 (EC 50 = 12.3 μM) [53], 3-oxabicyclo[3.2.0]heptane-typenucleoside 50 ( Figure 8) [54]. Unfortunately, no impressive results have been observed.…”

Direct Construction of Fused/Bridged 3D Rings via Visible‐Light Induced Dearomative Cycloaddition of Arenes

“…[3] Additionally, many other molecules bearing aliphatic fused or bridged 3D rings have proven potential for preclinical validation or clinical trials. [4] However, the assembly of such polycyclic moiety, especially high ring strained one, often requires elaborate multi-step synthetic operation, which is a rate-limiting factor in development of new drugs and synthesis of natural products. [5] The advancement of general and straightforward synthetic methods towards aliphatic fused or bridged 3D rings in terms of readily available feed-stock resources, convenient operation, good generality and environmental friendliness represents a subject of longstanding interest.…”