Cyclooctatetraene: A Bioactive Cubane Paradigm Complement

Abstract

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.

A novel vitamin K derived anticoagulant tolerant to genetic variations of vitamin K epoxide reductase

“…One of our long‐term goals has been to search for an improved VKA that is not susceptible to the genetic variations of VKOR with the hope that a fixed dose of anticoagulant would achieve the desired anticoagulation effect, despite the genetic backgrounds of patients. Recently, we have shown that replacing the phenyl group of warfarin with COT significantly decreased the variation of warfarin resistance among naturally occurring VKOR mutations 34 . However, the resistance of VKOR mutations to COT‐warfarin still had a more than 25‐fold difference.…”

“…Warfarin, vitamin K 1 , vitamin K 1 epoxide (KO), menadione, menaquinone‐4 (MK‐4), and MK‐4 epoxide were obtained from Sigma‐Aldrich (St. Louis, MO). Vitamin K derivatives (novel and known) were synthesized based on previously described methods 31‐36 . Synthetic procedures, full characterization, and copies of 1 H and 13 C nuclear magnetic resonance spectra can be found in Supporting Information.…”

“…Vitamin K derivatives (novel and known) were synthesized based on previously described methods. [31][32][33][34][35][36] Synthetic…”

Cubane Electrochemistry: Direct Conversion of Cubane Carboxylic Acids to Alkoxy Cubanes Using the Hofer–Moest Reaction under Flow Conditions

“…Eaton and co‐workers reported that photolysis of a dilute (0.03 m ) solution of 1,4‐diiodocubane in methanol afforded 1‐iodo‐4‐methoxycubane in 10 % yield . Subsequently, Irngartinger and later Williams and co‐workers improved the efficiency with photolysis yields up to 58 %, providing access to methoxycubanes as anisole isosteres.…”

“…As a further illustrative example, following Williams’ synthesis of a number of pravadoline analogues featuring anisole bioisosteres, the cubane derivative of the synthetic drug anisindione ( 30 ) was investigated. Anisindione ( 30 ), known under the brand name Miradon ® , is used as anticoagulant.…”