The principal aim of the proposed studies will be the bench-to-bedside development of polycyclic polyprenylated acylphloroglucinols (PPAPs) into a new class of anti-cancer drugs through comprehensive synthetic and biological investigations. We will develop a practical, efficient, and versatile strategy for enantioselective synthesis of significant quantities of PPAPs so that detailed biological and pharmacokinetic studies can be easily and reliably performed. Access to a library of PPAPs analogs and preparation of antibody-drug conjugates (ADCs) will facilitate the discovery of novel, highly potent, and uniquely selective anti-cancer drugs. Aim 1: Practical strategy for synthesis of PPAPs. T...

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The principal aim of the proposed studies will be the bench-to-bedside development of polycyclic polyprenylated acylphloroglucinols (PPAPs) into a new class of anti-cancer drugs through comprehensive synthetic and biological investigations. We will develop a practical, efficient, and versatile strategy for enantioselective synthesis of significant quantities of PPAPs so that detailed biological and pharmacokinetic studies can be easily and reliably performed. Access to a library of PPAPs analogs and preparation of antibody-drug conjugates (ADCs) will facilitate the discovery of novel, highly potent, and uniquely selective anti-cancer drugs.

Aim 1: Practical strategy for synthesis of PPAPs. Total synthesis of nemorosone. a) We will develop the first approach for Ni-catalyzed enantioselective prenyl conjugate additions to enones, which will be central to preparation of PPAPs. b) We will complete a concise, efficient, scalable, and practical total synthesis of nemorosone through a strategy that will enable us to access many PPAPs.

Aim 2: Synthesis of multigram quantities of PPAPs and biological studies. a) We will use our new approach for preparation of multigram quantities of several potent anti-cancer PPAPs. b) We will perform detailed studies regarding anti-cancer activity, mechanism of action, and metabolic stability of the new PPAPs in collaboration with Drs. Posner, Williams and Nijhawan at UT Southwestern Medical Center (UTSW).

Aim 3: Synthesis and biological evaluation of a library of analogs. a) We will assemble a library of PPAPs analogs adorned with non-natural functionalities and explore their use in ADCs. b) We will determine anti-neoplastic activity, protein targets, and pharmacokinetic profiles of the new entities in collaborations with Drs. Posner, Williams and Nijhawan at UTSW. We will evaluate permeability across the blood brain barrier in collaboration with Drs. Qin and Prakash at UT Dallas.

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