Design and synthesis of foscarnet-peptide conjugates, halogenated bisphosphonates and phosphonocarboxylates and biochemical sensing using film-bulk-acoustic-resonators

A practical method for synthesis and isolation of previously elusive deprotected P-N linked foscarnet-amino acid conjugates was developed. The conjugates are good candidates for evaluation as foscarnet prodrugs as they release the active drug quantitatively under physiological conditions leaving only benign amino acids as by-products.; A number of alkyl ester-protected thiophosphonoformate-peptide conjugates were synthesized via coupling between dimethyl-TPFACl and C-alkyl protected amino acids. An easily scalable, safe and cleaner method for synthesis of dimethyl-TPFACl was developed. The conjugates were treated with a series of dealkylating agents, such as t-BuNH2, NaOH, NaI, LiBr etc to produce monoanionic salts. Unfortunately, none of them led to the clean product due to competitive P-C and P-N bond cleavage.; A safe and convenient method for fluorination of phosphonoacetate derivatives was achieved using SelectfluorRTM as fluorine source. Using this reagent either mono- or difluoro analogs were obtained selectively by simple adjustment of base and SelectfluorRTM equivalents in the reaction mixture. The same reagent was used to prepare fluorinated analogs of nitrogen-containing bisphosphonates and phosphonoacarboxylates. Their corresponding chloro- and brominated analogs were also synthesized using N-chlorosuccinamide and N-bromosuccinamide, respectively, as Cl+ and Br+ sources.; For the first time, it was demonstrated that an FBAR device could be used for realtime observation of bio-molecular interactions, such as of biotin-streptavidin, on solid supports without use of labels. Sequence-specific DNA sensing was demonstrated by immobilizing probe DNA on the FBAR surface and measuring the resonance shift in real-time during hybridization with complementary strand. 15-Mer oligonucleotides differing by only one nucleobase could be distinguished. A highly sensitive thin gold film coated FBAR was developed, which was able to detect mercuric ion selectively in water as low as 0.2 ppb, below the maximum allowable concentration in drinking water in the US.