Spiralane: opening a new chapter of non-benzene pharmacy molecules
Sandra Forbes
Product Manager
Benzene ring is a key structural element in chemistry, as the most commonly used ring in natural products, bioactive compounds and drugs, it is difficult to find suitable replacements. Recently, a research team in Kiev, Ukraine, found that an organic molecule called heptane spiral [3.3] can be used as an ideal substitute for benzene rings in drug design.
This latest study shows that helical [3.3] heptane is used in chemistry as a unique three-dimensional shape scaffold, which can accurately simulate the single, intermediate and pairs of benzene rings in a non-collinear manner, perfectly meeting the needs of drug molecules for benzene rings.
Helical [3.3] heptane is usually synthesized by a linear method, and researchers have synthesized more than 40 functionalized helical [3.3] heptane compounds and introduced them into three FD-approved anticancer and antibacterial drugs, successfully replacing the benzene ring in the drug molecule. These "benzene-free" new drugs not only retain the therapeutic activity of the original drugs, but also improve some efficacy indicators.
Reaction conditions: (i) alkene (1 equiv.), amide (1 equiv.), triflic anhydride (1.2 equiv.), colliding or lutidine (1.2 equiv.), 1,2-dichloroethane, reflux, 16 h; (ii) aqueous NaHCO3; (iii) purification (vacuum distillation or column chromatography). The scale of the synthesis: a. 100-500 mg; b. 1-5 g; c. 10-40 g of the isolated product. d. With gaseous alkenes (products 1-3, 31-39), alkene component was taken in an excess. e. N, N-dimethylisobutyramide was used as a starting material instead of N, N-dimethylacetamide (DMA). X-ray crystal structure of compounds 18, 24, 30, and 41 are shown as thermal ellipsoids at 50% probability level; carbon – white, oxygen – red, nitrogen – blue, sulfur – yellow, bromine – orange, fluorine – green; hydrogen atoms are not shown.
X-ray crystallographic analysis also further verified the high three-dimensional structure of spiralane and the p-substituted benzene ring. Although the two are slightly different in some geometric parameters, this does not affect the important role of spiralane as a biological equivalent of the benzene ring.
The use of molecules such as spiralane to replace the benzene ring in drug molecules can optimize drug performance and create "benzene-free new drugs", which opens up broad chemical prospects and is a great progress in the field of medicine.
References
1. Kateryna Prysiazhniuk，Oleksandr P. Datsenko，et al. Spiro [3.3] heptane as a Non-collinear Benzene Bioisostere. DOI: 10.26434/chemrxiv-2023-djc05. https://doi.org/10.26434/chemrxiv-2023-djc05