About

Tadeusz Molinski, Ph.D., is a professor in the Department of Chemistry and Biochemistry at the Skaggs School of Pharmacy & Pharmaceutical Sciences. His research focuses on the structural, synthetic, and biological chemistry of marine natural products derived from marine sponges, ascidians, and environmental bacteria. He conducts chemical investigations and develops methods for discovering exceedingly small amounts of rare natural products using techniques such as NMR, circular dichroism, and mass spectrometry, as well as synthesizing drug-like analogs for therapeutic applications. His work includes the discovery of compounds with potential in cancer chemotherapy, antifungal agents, kinase and phosphatase inhibitors, calcium channel modulators, and targeted enzyme inhibitors for cancer and infectious diseases. Dr. Molinski has managed a high-visibility research effort for over 30 years, contributed to drug discovery and clinical medicine, and holds three patents related to his research. He has received numerous awards, including the Albert Hofmann Centennial Prize and the ACS Ernest Guenther Award in the Chemistry of Natural Products, and is a fellow of the AAAS and ASP.

Research topics

• Chemistry
• Stereochemistry
• Biology
• Combinatorial chemistry
• Biochemistry

Selected publications

• Correction: The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research

  HAL (Le Centre pour la Communication Scientifique Directe) · 2025-07-17

  articleOpen access

  Correction for 'The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research'

  PublisherOA PDFDOI

• The Enigma of Sponge-Derived Terpenoid Isothiocyanate–Thiocyanate Pairs: A Biosynthetic Proposal

  Marine Drugs · 2025-05-21 · 1 citations

  reviewOpen access1st authorCorresponding

  The co-occurrence of rare terpenoid thiocyanates (R-SCN), structurally similar to their more common isothiocyanate isomers (R-NCS), poses an enigma: how does the accepted path, terpenyl cation R+ → R-NC → R-NCS, accommodate R-SCN? The mystery can now be rationalized by the consideration of three biosynthetic motifs: terpenoid carbocation (R+) capture by cyanoformate, NC-COOH (itself in equilibrium with NC− and CO2); co-localized rhodanese (a dual-function enzyme) that can both convert fugitive inorganic NC− to thiocyanate ion, NCS−, and alkyl isonitriles to alkyl isothiocyanate (R-NC → R-NCS) and adventitious capture of the NCS− by R+. The former two scenarios explain the preponderance of isothiocyanates, R-NCS, as products of a linear reaction path—the α-addition of S0 to R-NC—and the third scenario explains minor, less stable thiocyanates, R-SCN, as products of the adventitious capture of liberated NCS− by the penultimate R+ precursor. DFT calculations support this proposal and eliminate other possibilities, e.g., the isomerization of R-NCS to R-SCN.

  PublisherOA PDFDOI

• Changing paradigms in natural product discovery: A molecule to microbe approach

  Phytochemistry Letters · 2025-10-01

  article
  PublisherDOI

• ‘Two neutrons walk into a bar’. The power of the 35Cl/37Cl isotope effect in structure elucidation of natural products by NMR and mass spectrometry

  Phytochemistry Letters · 2025-10-01

  article1st authorCorresponding
  PublisherDOI

• Structure-activity of Bastadins from the marine sponge Ianthella basta. Modulators of the RYR1 Ca2+ channel

  Bioorganic & Medicinal Chemistry Letters · 2025-03-03

  articleSenior authorCorresponding
  PublisherDOI

• The Enigma of Sponge-Derived Terpenoid Isothiocyanate-Thiocyanate Pairs. A Proposal for their Biosynthesis

  Preprints.org · 2025-01-21

  preprintOpen access1st authorCorresponding

  The co-occurrence of rare terpenoid thiocyanates (R-C-SCN), structurally similar to their more common isothiocyanate isomers (R-NCS) remained an enigma that can now be rationalized by consideration of three integrated biosynthetic motifs: terpenoid carbocation capture by cyanoformate, NC-COOH (itself in equilibrium with NC– and CO2), a co-localized rhodanese (a dual-function enzyme that can both convert inorganic NC– to thiocyanate ion, NCS–, and alkyl isonitriles to alkyl isothiocyanate (R-NC –> R–NCS). This scenario explains the preponderance of isothiocyanates, R-NCS as products of a linear reaction path – a-addition of S0 to R-NC – over the minor, less stable thiocyanates, R-SCN, as products of adventitious capture of liberated NCS– by the penultimate terpenoid carbocation precursor. DFT calculations support the proposal and eliminate other possibilities, e.g. isomerization of R-NCS to R-SCN.

  PublisherOA PDFDOI

• Designer tetrazine probes for chemical labeling of isocyanide-containing natural products

  ChemRxiv · 2025-04-08

  preprintOpen access

  The identification of novel antibacterial natural products (NPs) is paramount in confronting the global threat of antimicrobial resistance. New NPs with novel core structures and mechanisms of action (MoA) have become significantly more difficult to discover, as modern methods remain largely similar to those employed for decades. An alternative approach to classical bioactivity-guided isolation of NPs is chemical reactivity-guided isolation of NPs. Here, the reactivity of isocyanides with tetrazines via a [4+1] click reaction was exploited to establish a protocol for the detection and isolation of novel isocyanide-containing NPs using carefully designed tetrazine-based probes and contemporary metabolomics methods. Notably, these chemical probes can be used for the direct detection and isolation of primary, secondary, and tertiary isocyanides. Proof-of-concept was achieved, with the help of genome-mining, through the discovery of hazimycin in Kitasatospora purpeofusca. For this underexplored antibacterial agent, we further report on the biosynthesis, total synthesis, structure-activity relationship, metal-binding properties and antibacterial mechanism.

  PublisherOA PDFDOI

• The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research

  UNC Libraries · 2025-07-17

  articleOpen access

  Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.

  PublisherDOI

• Synthesis and Performance of <scp>l</scp>-Tryptophanamide and (<i>S</i>)-1-(Naphthalen-2′-yl)ethanamine-Based Marfey-Type Derivatives for Amino Acid Configurational Analysis: Diastereomeric Resolutions Directed by π–Cation Bonding

  The Journal of Organic Chemistry · 2025-02-20 · 1 citations

  articleOpen accessSenior authorCorresponding

  The configurational analysis of amino acids (AAs) in natural product peptides, often containing nonproteinogenic AAs, is mostly carried out by the venerable Marfey’s method using a chiral derivatizing agent (CDA) 1-fluoro-2,4-dinitrophenyl-5-l-alaninamide (l-FDAA)─Marfey’s reagent─which undergoes SNAr reaction of the 1° amino group. The resulting AA-DAA derivatives are mostly well-separated by reversed-phase HPLC, but some DAA derivatives resist resolution. Here, we report the synthesis and characterization of two CDAs: l-FDTA (4) in which the l-alanine-derived auxiliary is replaced by l-tryptophanamide and (S)-FDNE (3) where the auxiliary is S-(6-methoxynaphth-2-yl)-1-ethylamine. Side-by-side comparisons of the two reagents were carried out by AA derivatization and reversed-phase HPLC analysis with variables such as organic solvent, additives, and the ionic strength of the mobile phase. l-DTA derivatives of l- and d-AAs were found to show superior HPLC performance and an improvement in resolutions. When incorporated into the mobile phase, the ammonium ion (NH4+, 0–100 mM) showed a dramatic influence on differential retention times [ΔtR = ΔtRd – ΔtRl] of several key AAs. We attributed the effect to π–cation interactions between the indole ring of DTA and the NH4+ counterion in the analyte, a hypothesis supported by 1H NMR titrations and DFT calculations.

  PublisherDOI

• Empirical Chiroptical Analyses of Vicinal Bromochloro Natural Products by van’t Hoff’s Principle of Optical Superposition: Assignment of the C-16 Configurations of Callophycols A and B

  The Journal of Organic Chemistry · 2024-06-27 · 1 citations

  articleOpen access1st authorCorresponding

  A simple empirical method is described that allows the assignment of absolute configurations of natural products containing chiral vicinal bromochloro (VBC) units, including the bromochloro substituted isoprenyl units present in the structures of antiproliferative halomon (1a) and its halogen-swapped isomer iso-halomon (1b) from the red alga, Portieria hornemannii, and callophycols A (3) and B (4) from Callophycus serratus. The relative configurations of 3 and 4, published in 2007, were incomplete: C-16 was left unassigned. It is now shown that the additivity of molar rotations, [M]D (herein, abbreviated [M])─a consequence of van’t Hoff’s principle of optical superposition─could be used to deconvolute rotatory contributions, designated as [MX] and [MY] of the two remotely spaced chiral substructures within 3 and 4 using simple arithmetic. Input of proxy values, [M Y1] and [MY2], for the two different VBC units in two equations for [MX] and application of a “conditional test” returns the same value for [MX] only when a proxy with the correct configuration is included. It is revealed that 3 and 4 have opposite configurations at the C-16 stereocenter: 16S and 16R, respectively. Two important implications lie in these findings: 3 and 4 appear to qualify as paired-regioisomers, coupled through a putative dyotropic rearrangement (DR), and the biosyntheses of other Callophycus secondary metabolites, now numbering over 50, are tightly controlled by stereoelectronic considerations including neighboring group interactions of the DR. It now appears, counter to earlier suggestions, that the chirality of Callophycus secondary metabolites, despite their high chemodiversity, are surprisingly highly conserved. Enantiofacial halogenation additions to the C═C double bonds of precursor alkenes appear to direct the formation of the remaining stereocenters at both the halogenated benzoate-decalin core and the distal VBC of 3 and 4. A consistent hypothesis is proposed to account for macrolactonizations in other Callophycus natural products including bromophycolides A and B. The conditional test of molar rotations was applied in a different context to understand the chiroptical properties and trends observed in the highly iodinated meroditerpenes, iodocallophycols A–E, also from Callophycus sp., resulting in the revision of the configuration of callophycol E from (10R,14R) to (10S,14S).

  PublisherOA PDFDOI

Recent grants

• An Integrated Methodology for Nanomole-Scale Structure Elucidation of Natural Products

  NIH · $194k · 2018–2020

• NIH Grant S10RR025636

  NIH · $305k · 2011

• An Integrated Methodology for Nanomole-Scale Structure Elucidation of Natural Products

  NIH · $233k · 2018–2021

• Natural Products for Treatment of Emergent AIDS-Related Pathogens

  NIH · $1.9M · 2012–2018

• NIH Grant R01AI039987

  NIH · $3.2M · 2012

Frequent coauthors

• Brandon I. Morinaka

  National University of Singapore

  73 shared

• Doralyn S. Dalisay

  University of San Agustin

  72 shared

• John B. MacMillan

  57 shared

• Colin K. Skepper

  Novartis (United States)

  52 shared

• Makoto N. Masuno

  University of California, Davis

  48 shared

• Evan W. Rogers

  University of California, San Diego

  36 shared

• Isaac N. Pessah

  University of California, Davis

  33 shared

• Raymond J. Andersen

  31 shared

Education

• Bs (hon), School of Chemistry

  Monash University

  1978

Awards & honors

• Albert Hofmann Centennial Prize – elucidation of structures…
• Chair of the Gordon Conference in Marine Natural Products (2…
• Gordon Conference in Heterocyclic Compounds (2015)
• ACS Ernest Guenther Award in the Chemistry of Natural Produc…
• Fellow of the AAAS (2020)