Esters of all types (sulfonate, carboxylate and phosphate), as well as acetylenes, are important and valuable functional groups and key compounds in organic chemistry. Both serve as useful synthons in synthetic organic chemistry, they have been extensively employed in mechanistic studies and carboxylate and phosphate esters play a significant and vital role in biochemistry. Recently we had a breakthrough enabling us to combine these two simple and common organic functionalities into a single, unique, hitherto unknown, class of compounds, namely alkynyl esters. All three major types of esters: alkynyl sulfonate, RC is identical to COSO2Ar; carboxylate, RC is identical to COC(O)Ar; and phosphate RC is identical to COP(O)(OR')2, esters were prepared via tricoordinate iodonium species (RC is identical to C-I-Ph) + plus or minus (X=OTs, O2CAr, O2P(OR1)2). We shall capitalize on this breakthrough by exploring and developing the chemistry and biochemistry of our novel alkynyl esters and iodonium species. We shall investigate: a) the full scope and limitations of alkynyl ester synthesis, including functionalized substrates, via tricoordinate iodonium species; b) the use of alkynyliodonium species for the preparation of other hitherto unknown, or little known, functionalized acetylenes; c) the uses and chemistry of alkynyl esters such as alkynylating agents, cycloaddition reactions and ynolate (RC is identical to CO-) chemistry; d) the uses of alkynyliodonium species in synthetically useful reactions such as coupling with vinylcuprates to give conjugated, stereospecific enynes; e) the mechanism of the above processes. We will examine the biochemical and medicinal significance of these novel esters. Alkynyl carboxylates and phosphates will be examined as potential enzyme mediated inhibitors (""""""""suicide substrates"""""""") for esterases and proteases and phosphatases, respectively. Preliminary results indicate that CH3C is identical to COC(O)C6H5 is a potent inhibitor of Chymotrypsin and Trypsin (bovine pancreas), and most significant Cholinesterase (from electric eel). All new compounds will be submitted to the NCI for standard antitumor screening and evaluation. There is reason to believe that both the alkynyliodonium salts and alkynyl sulfonates might be a new class of potent antitumor agents via """"""""alkynylation"""""""" of biological nucleophiles. This program of fundamental research has major implications for synthetic organic, physical-organic, medicinal, and bio-organic chemistry.
|Banzon, J A; Kuo, J M; Fischer, D R et al. (1995) Histidine-254 is essential for the inactivation of phosphotriesterase with the alkynyl phosphate esters and diethyl pyrocarbonate. Biochemistry 34:750-4|
|Banzon, J A; Kuo, J M; Miles, B W et al. (1995) Mechanism-based inactivation of phosphotriesterase by reaction of a critical histidine with a ketene intermediate. Biochemistry 34:743-9|
|Segal, D; Shalitin, Y; Wingert, H et al. (1989) The interaction of alkynyl carboxylates with serine enzymes. A potent new class of serine enzyme inhibitors. FEBS Lett 247:217-20|