A nucleotide-analogue-induced gain of function corrects the error-prone nature of human DNA polymerase iota

Y-family DNA polymerases participate in replication stress and DNA damage tolerance mechanisms. The properties that allow these enzymes to copy past bulky adducts or distorted template DNA can result in a greater propensity for them to make mistakes. Of the four human Y-family members, human DNA polymerase iota (hpol?ι) is the most error-prone. In the current study, we elucidate the molecular basis for improving the fidelity of hpol?ι through use of the fixed-conformation nucleotide North-methanocarba-2'-deoxyadenosine triphosphate (N-MC-dATP). Three crystal structures were solved of hpol?ι in complex with DNA containing a template 2'-deoxythymidine (dT) paired with an incoming dNTP or modified nucleotide triphosphate. The ternary complex of hpol?ι inserting N-MC-dATP opposite dT reveals that the adenine ring is stabilized in the anti orientation about the pseudo-glycosyl torsion angle, which mimics precisely the mutagenic arrangement of dGTP:dT normally preferred by hpol?ι. The stabilized anti conformation occurs without notable contacts from the protein but likely results from constraints imposed by the bicyclo[3.1.0]hexane scaffold of the modified nucleotide. Unmodified dATP and South-MC-dATP each adopt syn glycosyl orientations to form Hoogsteen base pairs with dT. The Hoogsteen orientation exhibits weaker base-stacking interactions and is less catalytically favorable than anti N-MC-dATP. Thus, N-MC-dATP corrects the error-prone nature of hpol?ι by preventing the Hoogsteen base-pairing mode normally observed for hpol?ι-catalyzed insertion of dATP opposite dT. These results provide a previously unrecognized means of altering the efficiency and the fidelity of a human translesion DNA polymerase.     

Alpha decay theoretical calculations for 125-neutron nuclei

We have applied the new normalized and an older shell-model alpha decay theory to the calculation of decay rates of three 125-neutron isotones²⁰⁹Po,²¹¹Rn, and²¹³Ra. We also have applied the theory to the 2.1-ms isomer of²¹³Ra and are able thus to select a 17/2?assignment as preferable to the 13/2+ alternative.     

Synthesis of pyridyloxadiazoles 1. Characterization and thermal rearrangement of an unexpected 1,2,4-oxadiazol-5(4H)one

The synthesis of pyridyloxadiazoles by the reaction of acid chlorides with 5-(2-pyrklyl)-tetrazole or 2-pyridineamidoxime was studied. Reaction of 2-pyridineamidoxime with N,N-dimethylcarbamyl chloride produced 3-(2-pyridyl)-4-N,N-dimethylaminocarbony 1-1,2,4-oxadi-azol-5(4H)one instead of the expected oxadiazole. The oxadiazolone underwent thermal rearrangement with expulsion of carbon dioxide to yield the desired 3-(2-pyridyl)-5-N,N-dimethylamino-1,2,4-oxadiazole.     

Synthesis and structural characterization of tricarbonyl bis-[Di(N,N′'-allylamino)carbene]chromium and tungsten(0) complexes

Summary The reaction in situ of [M(CO)₆] (M = Cr or W), 1,2-bis(N-allylamino)ethane and CH(NMe₂)(OMe)₂ has resulted in the isolation of chelated metal carbene compounds in low yield. A [3,3] amino-Claisen rearrangement of a transient allyl electron-rich olefin, the organic precursor of the carbenes, appears to be the principal product. A single crystal X-ray diffraction study has shown that the tungsten complex has similar structural parameters to a molybdenum-carbene previously communicated. Detailed characterization of family six (G, No, W) chelated carbene compounds has been completed.     

Understanding how the herpes thymidine kinase orchestrates optimal sugar and nucleobase conformations to accommodate its substrate at the active site: a chemical approach

The herpes virus thymidine kinase (HSV-tk) is a critical enzyme for the activation of anti-HSV nucleosides. However, a successful therapeutic outcome depends not only on the activity of this enzyme but also on the ability of the compound(s) to interact effectively with cellular kinases and with the target viral or cellular DNA polymerases. Herein, we describe the synthesis and study of two nucleoside analogues built on a conformationally locked bicyclo[3.1.0]hexane template designed to investigate the conformational preferences of HSV-tk for the 2'-deoxyribose ring. Intimately associated with the conformation of the 2'-deoxyribose ring is the value of the C-N torsion angle chi, which positions the nucleobase into two different domains (syn or anti). The often-conflicting sugar and nucleobase conformational parameters were studied using North and South methanocarbadeoxythymidine analogues (6 and 7), which forced HSV-tk to make a clear choice in the conformation of the substrate. The results provide new insights into the mechanism of action of this enzyme, which cannot be gleaned from a static X-ray crystal structure.     

An improved method of synthesis of neplanocin and related cyclopentenyl-containing nucleosides

A facile one-step condensation of the cyclopentenyl α,-tosylate $\text{2c}$ with the alkali metal salts of 6-chloropurine and uracil, afforded the protected carbocyclic nucleosides $\text{5a}$ and $\text{8}$, respectively, which were converted to neplanocin a ($\text{6}$) and cyclopentenyl uracil ($\text{9}$) by established methods.     

Efficient synthesis of the C(1)-C(11) fragment of the tedanolides. The nonaldol aldol process in synthesis

[reaction: see text] The nonaldol aldol process developed in our laboratories has been applied to the synthesis of a C(1)-C(11) fragment 22 of the novel macrocyclic cytotoxic agents tedanolide and 13-deoxytedanolide 1 and 2. The commercially available hydroxy ester 7 was converted in 24 steps into compound 22 using two nonaldol aldol reactions.     

Wewakazole,a novel cyclic dodecapeptide from a Papua New Guinea Lyngbya majuscula

Phytochemical examination of a Papua New Guinea collection of Lyngbya majuscula resulted in the discovery of wewakazole (1), a novel cyclic dodecapeptide containing an unprecedented six five-membered heterocycles. Multiple NMR experiments and MS/MS data were required to assemble its planar structure because of its extensively signal-overlapped NMR spectra. In particular, a 1D HMBC was utilized to orient a three amino acid fragment that could not be placed by standard spectroscopic methods. [structure--see text]     

Emission frequency modulation by electronic confinement effect: Congo Red incorporated within a dendritic structure

We have investigated the photophysical properties of an organic dye (Congo Red) incorporated within the internal cavities of a dendrimer (type polypropylenimine of fifth-generation modified with a dense shell of amino acids). In this paper we show that the luminescence properties of Congo Red encapsulated into the "dendritic box" can be modulated by the electronic confinement effect. The emission frequencies of this organic dye incorporated within the dendritic structure can be red shifted with respect to their emission in solution, and the magnitude of this shifting can be modulated under appropriate experimental conditions.     

Biomimetic synthesis of the crispatene core

The biomimetic synthesis of the crispatene core is reported. The core framework was efficiently generated from an easily synthesized all (E)-tetraene precursor in one step, in good yield.