ABSTRACT
The design, synthesis and biophysical evaluation of two highly-constrained tricyclic analogues of locked nucleic acid (LNA), which restrict rotation around the C4'-C5'-exocyclic bond (torsion angle γ) and enhance hydrophobicity in the minor groove and along the major groove, are reported. A structural model that provides insights into the sugar-phosphate backbone conformations required for efficient hybridization to complementary nucleic acids is also presented.
Subject(s)
Drug Design , Oligonucleotides/chemistry , Molecular Conformation , Oligonucleotides/chemical synthesisABSTRACT
A constrained tricyclic analogue of α-L-LNA (2), which contains dual modes of conformational restriction about the ribose sugar moiety, has been synthesized and characterized by X-ray crystallography. Thermal denaturation experiments of oligonucleotide sequences containing this tricyclic α-L-LNA analogue (α-L-TriNA 2, 5) indicate that this modification is moderately stabilizing when paired with complementary DNA and RNA, but less stabilizing than both α-L-LNA (2) and α-L-TriNA 1 (4).
Subject(s)
Oligonucleotides/chemistry , Temperature , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Nucleic Acid Denaturation , Oligonucleotides/chemical synthesisABSTRACT
Heteroatom analogues of hydrocodone, in which the N-methyl functionality was replaced with oxygen, sulfur, sulfoxide, and sulfone, were prepared by a short sequence from the ethylene glycol ketal of hydrocodone; a carbocyclic analogue of bisnorhydrocodone was also prepared. The compounds were tested for receptor binding and revealed moderate levels of activity for the sulfone analogue of hydrocodone.
Subject(s)
Hydrocodone/chemical synthesis , Hydrocodone/pharmacology , Narcotic Antagonists , Animals , CHO Cells , Cricetinae , Cyclization , Dose-Response Relationship, Drug , Humans , Hydrocodone/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
Dual conformational restriction: a new, highly constrained modification of the α-L-locked nucleic acid (α-L-LNA) scaffold that locks the sugar furanose ring in an N-type configuration and also restricts rotation around torsion angle γ was synthesized. This new modification increases the thermostability of an oligonucleotide duplex compared to using a single mode of constraint alone.
Subject(s)
Nucleic Acids/chemistry , Oligonucleotides/chemistry , Models, Molecular , Molecular Structure , Nucleic Acid Conformation , Oligonucleotides/chemical synthesis , Stereoisomerism , Structure-Activity Relationship , ThermodynamicsABSTRACT
Our objective is to assess the accuracy of simulated quantum Monte Carlo electron distributions of atoms and molecules. Our approach is first to model the exact electron distribution by a linear combination of gamma distribution functions, with parameters chosen to exactly reproduce highly accurate literature values for a number of selected moments for the system of interest. In application to the ground-state electron distributions of helium and dihydrogen, a high level of accuracy of the model was confirmed upon comparing its predicted moments, not used in the model's parametrization, to those calculated from high-level theory. Next, we generated electron-electron and electron-nucleus distributions for dihydrogen from electron positions outputted from a variety of quantum Monte Carlo algorithms. Upon juxtaposition of the simulated distributions with the putatively exact one that we derived from the model, we quantified the error in simulated distributions. The most accurate distributions were obtained from no-compromise reptation quantum Monte Carlo, a recently developed algorithm designed to ameliorate the distributions' time-step bias. Marginally less accurate distributions were generated from fixed-node diffusion Monte Carlo with descendant counting and detailed balance.
