About

Dr. Ronald K. Castellano is the Colonel Allen R. and Margaret G. Crow Term Professor and Chair in the Department of Chemistry at the University of Florida. He received his B.S. degree in chemistry from Gettysburg College in 1995 and earned his Ph.D. in organic chemistry from the Massachusetts Institute of Technology in 2000, where he worked with Professor Julius Rebek, Jr. Following his doctoral studies, Dr. Castellano was an NSF International Research Scholars Postdoctoral Fellow for two years in the laboratory of the late Professor François Diederich at the Swiss Federal Institute of Technology (ETH) in Zürich. He joined the faculty at the University of Florida in 2002. Within the UF Chemistry Department, he served as Head of the Organic Division from 2012 to 2024 and became Department Chair in 2024. Dr. Castellano has been actively involved in the academic community, serving as Associate Editor for the Supramolecular Chemistry section of Frontiers in Chemistry starting in 2024, organizing the UF Chemathon from 2010 to 2024, and advising the UF Chemistry Club from 2009 to 2021. His contributions to mentoring and research have been recognized through several awards, including the UF Doctoral Dissertation Advising/Mentoring Award (2023–2024), designation as an IUPAC Young Observer in 2013, the UF-HHMI Science for Life Distinguished Mentor award in 2011, the Journal of Materials Science Emerging Investigator award in 2007, the National Science Foundation CAREER Award (2006–2011), and the Research Corporation Research Innovation Award in 2003.

Research topics

• Organic chemistry
• Chemistry
• Crystallography
• Computational chemistry
• Photochemistry

Selected publications

• [2.2]Paracyclophane–dicyanorhodanine conjugates as planar chiral molecular photoswitches

  Organic Chemistry Frontiers · 2025-10-28

  articleOpen accessSenior author

  photoisomerization. Ground-state (DFT) and excited-state (TD-DFT) calculations correlate well with the experimental geometries and the spectral (UV-vis and CD) characteristics, respectively. We are optimistic that the reported planar chiral [2.2]pCp-based photoswitches will facilitate the design of next-generation photoresponsive organic functional materials.

  PublisherOA PDFDOI

• US must support chemistry research

  Science · 2025-06-19

  letter
  PublisherDOI

• Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets

  Biomolecules · 2025-08-08 · 1 citations

  reviewOpen access

  Protein Disulfide Isomerases (PDIs) are emerging targets in anticancer therapy, with several PDI inhibitors demonstrating anticancer efficacy in preclinical models. Research has largely focused on "canonical" PDIs, such as PDIA1, which contain CXXC active site motifs where C represents Cysteine. Canonical PDIs have well-studied, critical roles in forming, breaking, and exchanging/scrambling disulfide bonds during protein folding. In contrast, non-canonical PDIs, which harbor CXXS active site motifs, remain less well-studied despite their role as sensors or effectors of protein folding quality control during protein trafficking in the secretory pathway. Here, we provide a review of the literature relating to the non-canonical PDIs ERp44, AGR2, and AGR3, which have been identified as strong dependencies in specific cancer subtypes according to the DepMap database. The biological and biochemical functions of ERp44, AGR2, and AGR3 are discussed, highlighting the role of ERp44 in two mechanisms of protein folding quality control, AGR2 as a selective sensor of mucin protein misfolding, and a unique role for AGR3 in cilia. Finally, we discuss recent efforts to develop small molecule inhibitors of ERp44, AGR2, and AGR3 as tool compounds and experimental therapeutics.

  PublisherOA PDFDOI

• Diagnosing the role of hydrogen bonding in the organization, aggregation, and optical properties of phthalhydrazide-functionalized molecules in solution and solid state

  New Journal of Chemistry · 2025-01-01

  articleOpen accessSenior authorCorresponding

  Reported are the consequences and complexities associated with installation of hydrogen-bonding functionality at the interior of π-conjugated oligomers to promote self-assembly in solution and morphological control in thin films.

  PublisherOA PDFDOI

• Figure S3 from DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress

  2025-07-02

  preprintOpen access

  <p>Supplementary Figure S3. Neither CDCP1 overexpression, or inhibition of eEF2 kinase influence DDA induction of DR5 upregulation, DR4/5 oligomerization, or Caspase 8 cleavage.</p>

  PublisherDOI

• Non-Canonical, Strongly Selective Protein Disulfide Isomerases as Anticancer Therapeutic Targets

  Preprints.org · 2025-05-15 · 1 citations

  preprintOpen access

  Protein Disulfide Isomerases (PDIs) are emerging targets in anticancer therapy, with several PDI inhibitors demonstrating anticancer efficacy in preclinical models. Research has largely focused on “canonical” PDIs, such as PDIA1, which contain CXXC active site motifs where C represents Cysteine. Canonical PDIs have well-studied, critical roles in forming, breaking, and exchanging/scrambling disulfide bonds during protein folding. In contrast, non-canonical PDIs, which harbor CXXS active site motifs, remain less well-studied despite their role as sensors or effectors of protein folding quality control during protein trafficking in the secretory pathway. Here, we provide a review of the literature relating to the non-canonical PDIs ERp44, AGR2, and AGR3, which have been identified as strong dependencies in specific cancer subtypes according to the DepMap database. The biological and biochemical functions of ERp44, AGR2, and AGR3 are discussed, highlighting the role of ERp44 in two mechanisms of protein folding quality control, AGR2 as a selective sensor of mucin protein misfolding, and a unique role for AGR3 in cilia. Finally, we discuss recent efforts to develop small molecule inhibitors of ERp44, AGR2, and AGR3 as tool compounds and experimental therapeutics.

  PublisherOA PDFDOI

• Beta-cyclodextrin formulation of a disulfide-bond disrupting agent for improved systemic exposure

  RSC Medicinal Chemistry · 2025-01-01

  articleOpen accessSenior author

  pharmacokinetics of DDAs following their complexation with CDs and provides an ameliorated approach for their oral administration in future animal studies.

  PublisherOA PDFDOI

• DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress

  Molecular Cancer Research · 2025-03-19 · 2 citations

  articleOpen access

  New agents are needed that selectively kill cancer cells without harming normal tissues. The TRAIL ligand and its receptors, DR5 and DR4, exhibit cancer-selective toxicity. TRAIL analogs or agonistic antibodies targeting these receptors are available but have not yet received FDA approval for cancer therapy. Small molecules for activating DR5 or DR4 independently of protein ligands may activate TRAIL receptors as a monotherapy or potentiate the efficacy of TRAIL analogs and agonistic antibodies. Previously described disulfide bond-disrupting agents activate DR5 by altering its disulfide bonding through inhibition of protein disulfide isomerases ERp44, AGR2, and PDIA1. Work presented in this article extends these findings by showing that disruption of single DR5 disulfide bonds causes high-level DR5 expression, disulfide-mediated clustering, and activation of caspase 8/caspase 3-mediated proapoptotic signaling. Recognition of the extracellular domain of DR5 by various antibodies is strongly influenced by the pattern of DR5 disulfide bonding, which has important implications for the use of agonistic DR5 antibodies for cancer therapy and as research tools. Importantly, other endoplasmic reticulum (ER) stressors, including thapsigargin and tunicamycin, also alter DR5 disulfide bonding in various cancer cell lines, and in some instances, DR5 mis-disulfide bonding is potentiated by overriding the integrated stress response (ISR) with inhibitors of the PERK kinase or the ISR inhibitor ISRIB. These observations indicate that the pattern of DR5 disulfide bonding functions as a sensor of ER stress and serves as an effector of proteotoxic stress by driving extrinsic apoptosis independently of extracellular ligands. IMPLICATIONS: Extreme ER stress triggers triage of transmembrane receptor production, whereby mitogenic receptors are downregulated and death receptors are simultaneously elevated.

  PublisherOA PDFDOI

• Figure S2 from DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress

  2025-07-02

  preprintOpen access

  <p>Supplementary Figure S2. Neither CDCP1 overexpression, or inhibition of eEF2 kinase influence DDA induction of DR5 upregulation, DR4/5 oligomerization, or Caspase 8 cleavage.</p>

  PublisherDOI

• Figure S4 from DR5 Disulfide Bonding Functions as a Sensor and Effector of Protein Folding Stress

  2025-07-02

  preprintOpen access

  <p>Supplementary Figure S4. DDAs upregulate TRAIL Decoy Receptor 2, an effect overridden by Cyclosporine A.</p>

  PublisherDOI

Recent grants

• CAREER: sigma-Coupled Donor-Acceptor Interactions in Self-Assembly

  NSF · $572k · 2006–2012

• Incorporating Tailored Hydrogen Bonding Interactions in Organic Optoelectronic Thin Films - Pursuing Universality of Form and Function

  NSF · $560k · 2019–2023

• Toward Mesoscale Order in Multicomponent Organic Thin Films via Hydrogen Bond Directed Supramolecular Topology

  NSF · $599k · 2015–2019

• Tautomerically Active Modules in Extended pi-Electron Systems

  NSF · $405k · 2011–2015

Frequent coauthors

• Khalil A. Abboud

  University of Florida

  57 shared

• Andrew J. Lampkins

  University of Florida

  45 shared

• Brian K. Law

  41 shared

• Coy D. Heldermon

  Florida College

  31 shared

• Renan B. Ferreira

  25 shared

• Mary E. Law

  University of Florida

  23 shared

• Ion Ghiviriga

  University of Florida

  22 shared

• Will R. Henderson

  22 shared

Labs

• Castellano LabPI

Education

• Ph.D., Chemistry

  University of Florida

  1995

• M.S., Chemistry

  University of Florida

  1992

• B.S., Chemistry

  University of Florida

  1990

Awards & honors

• UF Doctoral Dissertation Advising/Mentoring Award (2023–2024…
• University Term Professor (2016–2022)
• IUPAC Young Observer (2013)
• Research Corporation for Science Advancement Scialog Fellow…
• NSF CAREER Award (2006)