Oligothymidylate analogues having stereoregular, alternating methylphosphonate/phosphodiester backbones. Synthesis and physical studies.

P. S. Miller, N. Dreon, S. M. Pulford, K. B. McParland

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86 Scopus citations


Two decathymidylate analogues, d-(TpTp)4TpT-isomer 1 and isomer 2, having stereoregular, alternating methylphosphonate/phosphodiester backbones were prepared. The phosphodiester linkages of d-(TpTp)4TpT are cleaved slowly by snake venom phosphodiesterase in a stepwise manner, while slow random cleavage occurs with micrococcal nuclease which hydrolyzes isomer 2 faster than isomer 1. The CD spectra of isomer 1 and d-(Tp)9T are identical suggesting they have similar conformations, while that of isomer 2 shows an overall reduction of [theta]. Isomer 1 forms a 1T . 1A complex with poly(dA) and both 1T . 1A and 2T . 1A complexes with poly(rA), while isomer 2 forms a 2T . 1A complex of low thermal stability with poly(dA) and no complex with poly(rA). The Tm values of the partially nonionic d-(TpTp)4TpT . polynucleotide complexes are less dependent on salt concentration than are those of d-(Tp)9T. The stoichiometry and CD spectra of the complexes suggest that poly(dA) . isomer 1 duplex assumes a B-type geometry while isomer 2 . poly(dA) . isomer 2 triplex and the isomer 1 . poly(rA) complexes have an A-type geometry. Although there are no apparent differences between steric restrictions to rotation about the backbones of either isomer 1 or 2, or steric restrictions to complex formation, the results suggest that the configuration of the methylphosphate linkage controls: 1) interaction with nucleases, 2) oligomer conformation, and 3) interaction with polynucleotides. The latter effects may result from differences in solvation of the two isomers.

Original languageEnglish (US)
Pages (from-to)9659-9665
Number of pages7
JournalJournal of Biological Chemistry
Issue number20
StatePublished - Oct 25 1980

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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