Highly Precise Shape Mimicry by a Difluorotoluene Deoxynucleoside, a Replication‐Competent Substitute for Thymidine

Abstract

Until recently, the large majority of studies of the origins of DNA replication fidelity have concluded that complementarity of hydrogen bonding is the chief source of energetic selectivity between the four nucleotides at the transition state for initial insertion.[1,2] As part of this field of study, a wide number of modified nucleoside analogues have been incorporated into DNA in an effort to study the origins of mutagenesis and mechanisms for the fidelity of DNA replication.[3] Virtually all of these differed from natural nucleosides both in their hydrogen bonding arrangement and in their size and shape. While such approaches have led to valuable insights, with such analogues it is extremely difficult to distinguish between steric and hydrogen bonding effects as sources of observed differences in replication properties.[4,5]