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Department of Chemistry College of Liberal Arts and Sciences

Research

Synthetic and physical organic chemistry, from the weak interactions that direct self-assembly to the molecules that become medicines.

Cyclophane-Based Supramolecular Polymers

Cyclophanes hold two aromatic rings face to face, close enough to interact — an architecture that can be chiral without containing a single stereocenter. We use amide-functionalized [n.n]paracyclophanes as monomers for supramolecular polymers, where hydrogen bonding along the growing stack directs assembly. Small changes to the monomer have large consequences: the orientation of the amide groups determines whether hydrogen bonds alternate or self-sort, while bridge length and stereoelectronic effects tune how strongly monomers associate. Mixing monomers gives assemblies that emulate covalent copolymers. This work is funded by the National Science Foundation.

Related Publications

Comparison of alternating versus self-sorted hydrogen-bonding patterns in molecular structures showing different assembly motifs

Mixed Amide Paracyclophane Assemblies Emulating Supramolecular Copolymers. Cole D. Stearns,† Ajeet Kumar,† Ion Ghiviriga, Lukasz M. Dobrzycki, Khalil A. Abboud, and Ronald K. Castellano*. J. Am. Chem. Soc. 2025, 147, 24615.

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Chemical structures and space-filling models comparing dt[3.3]pCpTA-S and dt[3.3]pCpTA-SO2, tuning assembly with stereoelectronic effects

Tuning Supramolecular Polymer Assembly through Stereoelectronic Interactions. Will R. Henderson, Guancen Liu, Khalil A. Abboud, and Ronald K. Castellano*. J. Am. Chem. Soc. 2021, 143, 12688.

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Chemical structure of (±)-[n.p]pCpNTA N-centered amides transforming into helical polymers for n=2 and n=3

Influence of Amide Connectivity on the Hydrogen-Bond-Directed Self-Assembly of [n.n]Paracyclophanes. Will R. Henderson, Ajeet Kumar, Khalil A. Abboud, and Ronald K. Castellano*. Chem. Eur. J. 2020, 26, 17588.

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Small-Molecule Cancer Therapeutics

The “weak” inter- and intramolecular interactions that underlie synthetic supramolecular chemistry are also fundamental to enzyme structure, function, and targeting, and we bring the same physical organic approach to the design of new therapeutics. Recent work in our laboratory, together with Prof. Brian K. Law, has led to the discovery of the first inhibitors of the disulfide isomerases ERp44, PDIA1, and AGR2, termed Disulfide bond Disrupting Agents (DDAs). DDAs selectively kill cancer cells by simultaneously downregulating the HER-family receptors EGFR, HER2, and HER3 and by upregulating and activating Death Receptors 4 and 5 independently of their ligand TRAIL. DDAs exhibit striking anticancer activity in models of patient-derived, drug-resistant, metastatic breast cancer. This work is funded by the National Institutes of Health, the Florida Department of Health, Ocala Royal Dames for Cancer Research, Inc., and the Florida Breast Cancer Foundation.

Related Publications

Flowchart showing how DDAs target PDIs to downregulate EGFR, MET, and LRP5, and upregulate DR5 and TNFR1 to induce apoptosis

DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress. Mary E. Law,† Zaafir M. Dulloo,† Samantha R. Eggleston, Gregory P. Takacs, Grace M. Alexandrow, Young il Lee, Mengxiong Wang, Brian Hardy, Hanyu Su, Bianca Forsyth, Parag Das, Pran K. Datta, Chi-Wu Chiang, Abhisheak Sharma, Siva Rama Raju Kanumuri, Olga A. Guryanova, Jeffrey K. Harrison, Boaz Tirosh, Ronald K. Castellano*, and Brian K. Law*. Mol. Cancer Res. 2025, 23, 622.

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Chemical diagram showing an anti-cancer agent (DDA) binding to a host molecule with a binding constant Ka = 4080 M-1

Beta-cyclodextrin formulation of a disulfide-bond disrupting agent for improved systemic exposure. Zaafir M. Dulloo, Ion Ghiviriga, Mary E. Law, Sarvesh K. Verma, Abhisheak Sharma, Brian K. Law*, and Ronald K. Castellano*. RSC Med. Chem. 2025, 16, 3622.

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Diagram of chemical structures showing a correlation between thiol(ate) reactivity and anticancer activity

Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships. Amanda F. Ghilardi,† Elham Yaaghubi,† Renan B. Ferreira, Mary E. Law, Yinuo Yang, Bradley J. Davis, Christopher M. Schilson, Ion Ghiviriga, Adrian E. Roitberg, Brian K. Law*, and Ronald K. Castellano*. ChemMedChem 2022, 17, e202200165.

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Symmetrical Molecular Scaffolds for Rapid Functionalization

We have made synthetic and mechanistic contributions to the design of molecular scaffolds that allow the rapid and efficient preparation of discrete multifunctional architectures. Seminal work involves benzotrifuranone (BTF), a highly symmetric trilactone capable of one-pot sequential aminolysis to afford a trifunctionalized product. It joins only one other molecular reagent capable of useful single-pot trifunctionalization.

Related Publications

Chemical structure diagram showing energy transfer from 284 nm to 450 nm with approximately 80% energy transfer efficiency

A small molecule multi-FRET platform from benzotrifuranone. Ashton N. Bartley, Sadie F. DePeter, and Ronald K. Castellano*. Dyes Pigm. 2023, 220, 111732.

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Cover of Polymer Chemistry dated 28 April 2017, showing the benzotrifuranone trilactone at the centre surrounded by aromatic fragments and red polymer chains

Mild and efficient synthesis of ω,ω-heterodifunctionalized polymers and polymer bioconjugates. C. Adrian Figg, Ashton N. Bartley, Tomohiro Kubo, Bryan S. Tucker, Ronald K. Castellano*, and Brent S. Sumerlin*. Polym. Chem. 2017, 8, 2457.

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Reaction scheme showing benzotrifuranone undergoing two successive aminolysis reactions with amine, with relative rates per lactone of 390, 7.1 and 1.0 and ring strain falling from 27.9 to 17.5 to 8.4 kilocalories per mole

Selective and Sequential Aminolysis of Benzotrifuranone: Synergism of Electronic Effects and Ring Strain Gradient. Matthew B. Baker, Renan B. Ferreira, Jonathan Tasseroul, Andrew J. Lampkins, Alexandre Al Abbas, Khalil A. Abboud, and Ronald K. Castellano*. J. Org. Chem. 2016, 81, 9279.

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