The stilbene structure is part of many biologically active natural products, and these compounds can be attractive targets for chemical synthesis. A convergent synthetic design can be utilized in order to install the central olefinic moiety by way of organophosphorus compounds. This design has been employed to prepare a number of natural products, including the potent anti-cancer compounds known as the schweinfurthins and many analogues thereof. Not only do all these structures consist of a stilbenoid scaffold, but all are partially terpenoid in nature as well. Striking similarities to the schweinfurthins would become apparent following the isolation of a new group of compounds, which would later become known as the pawhuskins. In 2004, Belofsky and co-workers reported a small set of prenylated stilbenes that they named pawhuskins. Pawhuskins A-C were isolated from the common North American purple prairie clover (Dalea purpurea) collected near Pawhuska, Oklahoma. Belofsky's findings support an ethnomedical use, because the pawhuskins were shown to modulate opioid receptors through displacement of a nonselective radioactive antagonist (3[H]-naloxone) striatal tissue taken from rat brain. Pawhuskin A was the most potent member of the family, making it one of a small group of compounds that does not contain a basic nitrogen atom but that still exhibits effects on the opiate receptor system. This activity is surprising given the absence of the traditional pharmacophore, a 6-membered piperidine ring containing a basic nitrogen. In these studies, we will report the opioid receptor binding affinity and selectivity of pawhuskin A using a functional assay based on [35S]GTP-γ-S binding. Because of our well-established history of synthesizing prenylated stilbenes, and the unique biological activity of the pawhuskins, we embarked on a synthetic effort targeted at pawhuskin analogues. The preparation of sixteen analogues will be presented. The structure-activity relationship studies of twenty compounds correlated to illuminate more information on the novel pawhuskin pharmacophore will also be reported. Efforts toward preparation of more water-soluble structures similar to the pawhuskins will also be described. The interrelated studies involving pawhuskin analogue synthesis and elucidation of the novel pharmacophore, as well as interesting chemical findings, will be discussed in detail.

Living organisms are capable of producing novel terpenoids with both remarkable ease and great selectivity. Many of these natural products exhibit significant biological activity useful for treatment of human diseases, but isolation of highly sought chemicals often results in only minute quantities. Consequently, extraction of these potential therapeutics from natural sources becomes an unrealistic method for obtaining enough material for a thorough biological evaluation, and so synthesizing these compounds becomes essential. Synthesis of terpenoids as potential therapeutics requires exceptional selectivity, especially when corresponding isomers elicit a contrasting biological response. The necessity for such selective syntheses along with the inherent structural complexities of terpenoids, often presents a number of significant challenges for the synthetic chemist. Isolation of the terpenoids pawhuskins A–C and petalostemumol from Dalea purpurea was reported by Belofsky in 2004, and of the collected compounds pawhuskin A was found to exhibit the most significant activity in an opioid receptor assay in vitro. Natural pawhuskin A was extracted from “Purple Prairie Clover” in only a 39 mg quantity and therefore syntheses of the natural product along with several analogues were pursued. Two of the synthesized analogues demonstrated greater potency than pawhuskin A, and interestingly these two isomeric derivatives were found to be selective for two different opioid receptors. However, the synthetic route utilized to form these two derivatives was not very selective for either isomer, and thorough purification proved challenging. Ergo, an alternative approach was sought to ensure the purity of these potential therapeutics. Parallel syntheses affording high selectivity for the key isomeric intermediates as well as a third regioisomer have been developed. The new isomeric intermediate also allowed the synthesis of two new analogues. This work is described in this report along with the formation of additional pawhuskin derivatives. The activity of these analogues as opioid receptor modulators also will be discussed.