John S. Driscoll

Conformational changes of small molecules binding to proteins

Flexible molecules change their conformation upon binding to a protein. This was shown by the analysis of small molecules whose structures have been determined by X-ray crystallography of both the pure compound and the compound bound to a protein. Thirty-three compounds present both in the Cambridge Structural Database and the Brookhaven Protein Data Bank were analyzed, and both were compared with the global energy minimum conformation calculated by the molecular mechanics program CHARMm. It was found that the conformation bound to the protein differs from that in the crystal structure and also from that of the global energy minimum, and the degree of deformation depends upon the number of freely rotatable bonds in the molecule. Analysis of the conformational energies of the flexible molecules showed that, for most of those compounds, both the crystal and the protein-bound conformations are energetically well above the global minimum, and, in many cases, not even in any local energy minimum. Semi-empirical calculations performed for a select number of structures, using both the AM1 and PM3 hamiltonians, confirmed these results. These findings are discussed as to their impact upon contemporary methods of drug design.

National Cancer Institute Drug Information System 3D database

A searcheable database of three-dimensional structures has been developed from the chemistry database of the NCI Drug Information System (DIS), a file of about 450,000 primarily organic compounds which have been tested by NCI for anticancer activity. The DIS database is very similar in size and content to the proprietary databases used in the pharmaceutical industry; its development began in the 1950s; and this history led to a number of problems in the generation of 3D structures.

The use of macromolecules as carriers of antitumor drugs

Abstract The purpose of this investigation is an extension of the use of protein carriers to various types of antitumor drugs, including antimetabolites and antitumor antibiotics. The variety of carriers has also been increased by the use of branched chain synthetic polymers with a poly- l -lysine backbone. Most drug-protein combinations were non-covalent in nature. Murine antitumor results are discussed based on the evaluation of activity in the leukemia L 1210 and P 388 systems. In several cases the therapeutic efficacy of an antitumor drug was increased by macromolecular complexation. This effect was partly due to reduced toxicity and seems to be dependent on the choice of carrier as well as the choice of drug. Actinomycin D, cytosine arabinoside, 5 -azacytidine and dichloromethotrexate appear to be good candidates for a macromolecular complex approach to cancer chemotherapy.

A diastereoselective synthesis of (S,S)-α-fluoro-2,2-dimethyl-1,3-dioxolane-4-propanoic acid methyl ester, a key intermediate for the preparation of anti-HIV effective fluorodideoxynucleosides

(S,S)-α-fluoro-2,2-dimethyl-1,3-dioxolane-4-propanoic acid methyl ester (10), a key intermediate for the preparation of anti-HIV active 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (1, FddA) and 1-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)cytosine (2, FddC) was prepared via the diastereoselective fluorination of the chiral imide enolate obtained from 8 with N-fluorobenzenesulfonimide. The overall yield of 10 from the readily available 1,2:5,6-di-O-isopropylidene-D-mannitol was 25% (de 93%).

Synthesis of 2′,3′-Dideoxycyclopentenyl Carbocyclic Nucleosides as Potential Drugs for the Treatment of AIDS

Abstract The recently discovered antiviral activity of 2′,3′-dideoxy-nucleosides against the AIDS virus in vitro prompted the synthesis of 2′,3′-dideoxycyclopentenyl adenine and cytosine. A sequence of two consecutive reductive deoxygenations using 1,1′-thiocarbonyldiimidazole followed by reduction with tributyl tin hydride afforded the desired target compounds. Neither compound showed activity in the in vitro assay against the HTLV-III/LAV virus.

Comparison of the activity of Arabinosyl-5-azacytosine, Arabinosyl cytosine, and 5-azacytidine against intracerebrally implanted L1210 leukemia

SummaryArabinosyl-5-azacytosine (ara-AC) is a new compound which combines the structural characteristics of arabinosyl cytosine (ara-C) and 5-azacytidine (5-AC). These three compounds, injected intraperitoneally, were evaluated in direct comparison against the intracerebral L1210 leukemia model. 5-AC was active in a non-schedule dependent manner producing increase in life span (ILS) values of 70%. The effects of both araC and ara-AC were schedule-dependent with the best activity (ILS ca. 600%; multiple long term survivors) observed using an around-the-clock treatment schedule. In all experiments, ara-AC appeared to be more efficacious than ara-C. In some instances, ara-AC was as active as the positive control compound, BCNU. Excellent activity for ara-AC was also observed against the intracerebral P388 leukemia system.

A new synthetic approach to the clinically useful, anti-HIV-active nucleoside, 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (β-FddA). Introduction of a 2′-β-fluoro substituent via inversion of a readily obtainable 2′-α-fluoro isomer

A convenient route to the anti-HIV active compound, 9-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)adenine (1, β-FddA) started with the facile introduction of fluorine at C2′ from the α-side of protected 9-(β-D-arabinofuranosyl)adenine (ara-A). Inversion of the stereochemistry at C2′ was accomplished via a stable vinyl intermediate (6), which underwent stereoselective reduction of the double bond to give the desired 2′-F-threo isomer with the opposite β-fluoro stereochemistry.

The “β-Fluorine Effect” in the Non-Metal Hydride Radical Deoxygenation of Fluorine-Containing Nucleoside Xanthates

Abstract An alternative method to conduct a Barton-McCombie deoxygenation in nucleosides is described. The utility of the procedure is limited to structures with an electronegative substituent, particularly fluorine, in the β-position relative to the radical center. The process is radical in nature and triggered by peroxides. The abstraction of hydrogen from the solvent is favorably influenced by the presence of a β-fluorine.

Chemistry and Anti-HIV Activity of 2′-β-Fluoro-2′,3′-dideoxyguanosine

Abstract The 2′-β-fluoro analogue of 2′,3′-dideoxyguanosine has been prepared by two synthetic routes. This compound and two analogues have anti-HIV activity in at least two of three host cell systems used (ATH8, CEM, PBL). These compounds, as well as their ddGuo parents, have been characterized with regard to their acid-stabilities, octanol-water partition coefficients, and enzyme substrate properties for adenosine deaminase and purine nucleoside phosphorylase. F-ddGuo analogues are less potent but more stable than their non-fluorinated parent compounds.

Rearrangement and elimination reactions in 1,2,4-triazole derivatives

Four possible nucleophilic sites are available when 3-amino-1,2,4-triazole (4) reacts with isocyanates or alkylating agents. In the reaction with ethoxycarbonyl isothiocyanate at 22°, addition to a ring nitrogen took place yielding 5-amino-1-[ethoxycarbonylarnino(thiocarbonyl)]-1,2,4-triazole (1). The rearrangement of compound (1) to the amino-substituted isomer (2) in dimethylformamide was followed by n.m.r. spectroscopy and found to be complete in 34 min under ambient conditions. In pyridine solution compound (1) reacted differently, with HNCS elimination, to give 5-amino-1-ethoxycarbonyl-1,2,4-triazole (3). Two additional isomers of (3) were prepared, by the rearrangement of (3) and by the low temperature reaction of (4) with ethyl chloroformate. The carbonyl analogues of (1) and (2) were prepared by use of the analogous isocyanate. The ring-substituted carbonyl compound rearranged more slowly to the amino-substituted isomer than did compound (1), and elimination of HNCO was not observed. Both carbonyl analogues were cyclised to [1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-dione (5-azaxanthine). Two methylaminocarbonyl derivatives of (4) were also prepared, isolated, and characterized.