Biomedical subjects
Publications and source records attributed to Nicholas A Boyle.
[reaction: see text] Since the first disclosure of difluoromethylenediphosphonate, 2, almost 40 years ago, interest in this compound has flourished in several research areas. In this paper, we present a convenient, high-yielding (99% overall) method for the preparation of milligram to multigram quantities of 2 (as the bis(tributylammonium salt, 2b) in a solid form that is easy to handle.
The triphosphates of antiviral 2',3'-dideoxynucleosides (ddNs) are the active chemical species that inhibit viral DNA synthesis. The inhibition involves incorporation of ddNMP into DNA and subsequent chain termination. A conceivable strategy for antiviral drugs is to employ nucleoside 5'-triphosphate mimics that can entirely bypass cellular phosphorylation. AZT 5'-alpha-R(P)-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaB-betagammaCF(2)TP) has been identified as a potent inhibitor of HIV-1 reverse transcriptase (HIV-1 RT). This work was aimed at confirming that 5'-alphaB-betagammaCF(2)TP is a useful generic triphosphate moiety and can render antiviral ddNs with potent inhibitory effects on HIV-1 RT. Thus, 10 ddNs were converted to their 5'-alphaB-betagammaCF(2)TPs via a sequence (one-pot) of reactions: formation of an activated phosphite, formation of a cyclic triphosphate, boronation, and hydrolysis. Other synthetic routes were also explored. All ddN 5'-alphaB-betagammaCF(2)TPs tested exhibited essentially the same level of inhibition of HIV-1 RT as the corresponding ddNTPs. A conclusion can be made that 5'-alphaB-betagammaCF(2)TP is a generic and promising triphosphate mimic (P3M) concerning HIV-1 RT inhibition and serum stability. It is anticipated that use of 5'-alphaB-betagammaCF(2)TP as P3M moiety will lead to the discovery of a new class of anti-HIV agents.
Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-Rp-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaBCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT. Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma(difluoromethylene)triphosphate mimics with either a non-bridging calphaP-thio (5'-alphaSCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene)triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (Ki = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.
Preparation of the key intermediate carboxydifluoromethanesulfonamide provides direct synthetic access to a wide range of novel difluoromethanesulfonamides, including the acetazolamide analogue (2-ethanoylamino-1,3,4-thiadiazol-5-yl)-difluoromethanesulfonamide. Their water solubility and stability, ether partition coefficient, pK(a) and submicromolar dissociation constants for human carbonic anhydrase isozyme II (HCA II) make them promising candidates for topical glaucoma therapy.
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Methods for combinatorial and parallel synthesis continue to evolve in order to meet the demands of modern synthetic organic chemistry. The nature of the support, while typically overlooked, is a key consideration for successful combinatorial organic synthesis. Developments in combinatorial synthesis technologies such as the 'lab-on-a-chip' concept and 96-well-plate-compatible resin plugs have been reported, which should contribute to meeting the increasing challenges of this field.
The replacement of the amide bond in a peptide backbone is a widely used form of peptide mimicry. Several of the most common amide bond surrogates, including peptidomimetic work done in this laboratory, and their biological applications are presented in this review.