Design, Synthesis, and Optimization of Small-Molecule CD4 Mimetics As HIV-1 Entry Inhibitors and Synthetic Efforts Toward the Total Synthesis of Nahuoic Acid C_ii Hung-Ching Chen

Format:

Book

Thesis/Dissertation

Author/Creator:

Chen, Hung-Ching, author.

Contributor:

University of Pennsylvania. Chemistry., degree granting institution.

Language:

English

Subjects (All):

0431.

0485.

0487.

0490.

Local Subjects:

0431.

0485.

0487.

0490.

Physical Description:

1 electronic resource (251 pages)

Contained In:

Dissertations Abstracts International 87-07B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

This thesis comprises two independent parts.Part I:The persistent challenge of human immunodeficiency virus (HIV-1) eradication is driven in part by the virus's capacity to evade immune recognition through conformational masking of its envelope glycoprotein (Env). Small-molecule CD4 mimetic compounds (CD4mcs) represent a promising strategy that blocks viral entry by binding to the conserved Phe43 cavity of gp120, thereby competing with native CD4 for Env engagement. Beyond direct entry inhibition, CD4mcs induce conformational rearrangements that expose normally occluded epitopes on gp120, sensitizing infected cells to antibody-dependent cellular cytotoxicity (ADCC).This work describes the rational design, synthesis, and evaluation of novel CD4mc analogs aimed at improving antiviral potency, breadth, and physicochemical properties. Quaternary analogs were synthesized to enable direct engagement with the highly conserved gp120 residue Asp368. Although biological evaluation revealed agonistic rather than antagonistic activity, these studies confirmed that Asp368 is accessible through substitution at the C1 position via a three-carbon linker, thereby establishing critical design principles for future dual-residue targeting.Secondly, to support preclinical advancement of lead compounds, a concise and scalable synthesis of the next-generation indoline CD4mc, CJF-III-288, was established. The revised route streamlined the overall sequence, minimized reliance on chromatographic purification, and enabled multigram production (>20 g) suitable for in-vivo studies. Collectively, these studies advance the development of CD4mcs as dual-function HIV-1 inhibitors that both block viral entry and enhance immune clearance, with significant implications for future functional cure strategies.Part II:The Nahuoic acids are polyhydroxylated polyketides defined by a cis-decalin core fused to a highly oxygenated polyol side chain. First isolated from marine Streptomyces strains, these metabolites attracted significant attention as the only natural products reported to selectively and competitively inhibit the histone methyltransferase SETD8, a key epigenetic regulator implicated in cancer progression. Their stereochemical complexity and biological potential have made them compelling synthetic targets.This work details ongoing efforts toward the total synthesis of Nahuoic Acid Cii, pursued through a convergent strategy that unites two advanced fragments. The polyol-alkyne side chain was assembled via Type II Anion Relay Chemistry (ARC), while the cis-decalin core was constructed through a Ti-TADDOLate-catalyzed asymmetric Diels-Alder reaction. To replace the traditional mercury-based protocol, a visible-light Eosin Y-mediated photocatalytic method was developed for dithiane/TMS deprotection, providing a sustainable and environmentally benign alternative without loss of efficiency. The cis-decalin fragment synthesis was further streamlined through PtO2-catalyzed selective hydrogenation, eliminating redundant steps and improving overall step economy. The two fragments were united by a Micalizio alkoxide-directed alkyne-allylic alcohol coupling, forging the critical C-C bond with high stereoselectivity. Olefin metathesis using an alternative substrate envisioned to overcome the challenges previously encountered in ester installation and thereby complete the total synthesis of Nahuoic Acid Cii

Notes:

Advisors: Smith, Amos B., III; Trauner, Dirk Committee members: Chenoweth, David M.; Walsh, Patrick; Kozlowski, Marisa

Source: Dissertations Abstracts International, Volume: 87-07, Section: B.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276004693

Access Restriction:

Restricted for use by site license