Biomedical subjects

John A Montgomery

Publications and source records attributed to John A Montgomery.

6 recordsLinked to original sources

PubMed2006

A restricted-open-shell complete-basis-set model chemistry.

A restricted-open-shell model chemistry based on the complete basis set-quadratic Becke3 (CBS-QB3) model is formulated and denoted ROCBS-QB3. As the name implies, this method uses spin-restricted wave functions, both for the direct calculations of the various components of the electronic energy and for extrapolating the correlation energy to the complete-basis-set limit. These modifications eliminate the need for empirical corrections that are incorporated in standard CBS-QB3 to compensate for spin contamination when spin-unrestricted wave functions are used. We employ an initial test set of 19 severely spin-contaminated species including doublet radicals and both singlet and triplet biradicals. The mean absolute deviation (MAD) from experiment for the new ROCBS-QB3 model (3.6+/-1.5 kJ mol(-1)) is slightly smaller than that of the standard unrestricted CBS-QB3 version (4.8+/-1.5 kJ mol(-1)) and substantially smaller than the MAD for the unrestricted CBS-QB3 before inclusion of the spin correction (16.1+/-1.5 kJ mol(-1)). However, when applied to calculate the heats of formation at 298 K for the moderately spin-contaminated radicals in the G2/97 test set, ROCBS-QB3 does not perform quite as well as the standard unrestricted CBS-QB3, with a MAD from experiment of 3.8+/-1.6 kJ mol(-1) (compared with 2.9+/-1.6 kJ mol(-1) for standard CBS-QB3). ROCBS-QB3 performs marginally better than standard CBS-QB3 for the G2/97 set of ionization energies with a MAD of 4.1+/-0.1 kJ mol(-1) (compared with 4.4+/-0.1 kJ mol(-1)) and electron affinities with a MAD of 3.9+/-0.2 kJ mol(-1) (compared with 4.3+/-0.2 kJ mol(-1)), but the differences in MAD values are comparable to the experimental uncertainties. Our overall conclusion is that ROCBS-QB3 eliminates the spin correction in standard CBS-QB3 with no loss in accuracy.

Journal Article↗

PubMed2005

Synthesis and biological activity of 4'-thio-L-xylofuranosyl purine nucleosides.

A series of some new 4'-thio-L-xylofuranosyl nucleosides were prepared and evaluated as potential anticancer agents. A versatile sugar intermediate for direct coupling with the purine moiety is also synthesized by an efficient and high-yielding route. Proof of structure and configuration at all chiral centers of the nucleosides was obtained by proton NMR. All target compounds were evaluated in a series of human cancer cell lines in vitro. The details of the synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-L-xylofuranose (6) and corresponding purine nucleosides are presented in the manuscript.

Antineoplastic Agents↗

PubMed2003

Preclinical antitumor activity of 4'-thio-beta-D-arabinofuranosylcytosine (4'-thio-ara-C).

PURPOSE: 4'-Thio-beta -d-arabinofuranosylcytosine (4'-thio-ara-C), which has shown significant cytotoxicity against a panel of human tumor lines, was evaluated for antitumor activity against a spectrum of human tumor systems in mice. METHODS: Antitumor activity was evaluated in 15 subcutaneously implanted human tumor xenografts. 4'-Thio-ara-C was administered intraperitoneally using either q1dx9 (daily treatment for nine consecutive days) or q4hx3/q1dx9 (three treatments each day separated by 4-h intervals for nine consecutive days). RESULTS: 4'-Thio-ara-C exhibited an excellent spectrum of activity. Treatment with the compound was curative against HCT-116 colon, SW-620 colon, NCI-H23 NSCL, and CAKI-1 renal tumors and resulted in partial/complete regressions in the DLD-1 colon, NCI-H522 NSCL, DU-145 prostate, and PANC-1 pancreatic tumor models. Tumor stasis was noted for HT29 colon and NCI-H460 NSCL tumors. Tumor inhibition was observed for A549 NSCL, PC-3 prostate, LNCAP prostate, and MDA-MB-435 breast tumors. Of the 15 tumors examined, only CFPAC-1 pancreatic was unresponsive to the compound. In contrast, 1-beta -d-arabinofuranosylcytosine was minimally active at best against CAKI-1 renal, HCT-116 colon, NCI-H460 NSCL, and SW-620 colon tumors. Schedule- and route-dependency studies were conducted using the NCI-H460 NSCL tumor. The activity of 4'-thio-ara-C was independent of schedule when comparing q2dx5 (every other day for five treatments), q1dx9, and q4hx3/q1dx9 treatment schedules. 4'-Thio-ara-C was equally effective by the intravenous and intraperitoneal routes of administration, with the oral route being less efficacious. CONCLUSIONS: On the basis of these results, 4'-thio-ara-C appears to have a profile distinct from other nucleoside antitumor agents and is being advanced to clinical trials.

Animals↗

PubMed2003

Synthesis and anti-cancer activity of some novel 5-azacytosine nucleosides.

1-O-Acetyl-2-deoxy-3,5-di-O-toluoyl-4-thio-D-erythro-pentofuranose and 2-deoxy-1,3,5-tri-O-acetyl-4-thio-L-threo-pentofuranose were coupled with 5-azacytosine to obtain alpha and beta anomers of nucleosides. All four nucleosides were reduced to the corresponding dihydro derivatives and deblocked to give target compounds. All eight target compounds were evaluated in a series of human cancer cell lines in culture. Only 2'-deoxy-4'-thio-5-azacytidine (3beta) was found to be cytotoxic in all the cell lines and was further evaluated in vivo. Details of the synthesis and biological activity are reported.

Antineoplastic Agents↗

PubMed2002

Enhancement of nucleoside cytotoxicity through nucleotide prodrugs.

A common reason for the lack of cytotoxicity of certain nucleosides is thought to be their inability to be initially activated to the monophosphate level by a nucleoside kinase or other activating enzyme. In a search for other nucleosides that might be worthwhile anticancer agents, we have begun to examine the utilization of monophosphate prodrugs in order to explore whether any enhanced cytotoxicity might be found for the prodrugs of candidate nucleosides that have little or no cytotoxicity. To that end, 5'-bis(pivaloyloxymethyl) phosphate prodrugs of two weakly cytotoxic compounds, 8-aza-2'-deoxyadenosine (5) and 8-bromo-2'-deoxyadenosine (9), have been prepared. These prodrugs (8 and 12) were examined for their cytotoxicity in CEM cells and were found to possess significantly enhanced cytotoxicity when compared with the corresponding parent nucleosides. Further cell culture experiments were conducted to gain insight into the mechanisms of cytotoxicity of these two prodrugs, and those data are reported.

Adenosine Monophosphate↗

PubMedDate not supplied

Selective metalation of 6-methylpurines: synthesis of 6-fluoromethylpurines and related nucleosides.

A selective metalation at the 6-CH3 over C-8 of 6-methylpurine derivative 6 was observed with softer counter cation (Na+ or K+) of the base, while the harder Li+ showed no selectivity. In the presence of N-fluorobenzenesulfonamide (NFSI), this property was utilized for the synthesis of 6-fluoromethylpurine derivatives 4 and 5 as potential toxins for suicide gene therapy.

Genetic Therapy↗