Compendium

Medicinal Chemistry and Photochemistry

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Medicinal Chemistry and Photochemistry

A Tier 2 specialty bundle covering two adjacent areas of applied chemistry: the discovery and optimization of pharmaceutical small molecules (medicinal chemistry) and the chemistry of light-driven processes (photochemistry). The two share more overlap than convention suggests — photoredox catalysis is now a routine medicinal chemistry tool, photodynamic therapy is a clinical modality, photoaffinity probes are central to target identification, and photo-protecting groups enable spatial-temporal control of bioactive molecules.

Part I — Medicinal Chemistry

Drug discovery cascade

The pharmaceutical pipeline runs target identification → hit identification → lead optimization → preclinical (IND-enabling) → Phase 1 (safety, ~30 healthy volunteers) → Phase 2 (efficacy + dose ranging, ~100-300 patients) → Phase 3 (pivotal, ~1000-3000 patients) → NDA (New Drug Application; small molecules) or BLA (Biologics License Application; biologics) → FDA / EMA / PMDA approval → Phase 4 post-marketing surveillance.

Modern hit-to-marketed-drug rates run roughly 1-3% of compounds entering hit-to-lead, with lead-to-drug timelines of 5-10 years and average capitalized R&D cost of approximately USD 2.5 billion (DiMasi, Grabowski, Hansen 2016, Journal of Health Economics — “Innovation in the pharmaceutical industry: New estimates of R&D costs”). Phase 2 efficacy failures are the largest single attrition cause; oncology Phase 3 success rates are notably lower (~5%) than infectious disease or metabolic.

Hit identification methods

HTS — high-throughput screening. Robotic plate-based assays running 100k–2 million compounds against a biochemical or cellular endpoint. Pioneered at Merck, Pfizer, Lilly in the 1990s; persistent at most major pharma but increasingly supplemented by encoded library and virtual screening approaches due to hit-rate decline.

DEL — DNA-encoded library screening. Halpin and Harbury (2004, PLoS Biology — “DNA display I/II/III”) introduced split-and-pool DNA-encoded synthesis; commercial scale by Nuevolution (Copenhagen; acquired by Amgen 2019), X-Chem (Waltham MA), HitGen (Chengdu), Vipergen (Copenhagen). Single libraries now exceed 1 billion compounds; selection against immobilized target with PCR readout. Mid-2020s applications: GPCRs, kinases, and undruggable surfaces like K-Ras.

FBDD — fragment-based drug discovery. Astex Pharmaceuticals (Cambridge UK, founded 2000; pioneered Pyramid platform) plus Plexxikon (Berkeley; PLX4032 vemurafenib origin), SPRINT, Vernalis. Screen 1k–10k low-MW fragments (~150–250 Da) by SPR, NMR (1H-15N HSQC; STD-NMR), or X-ray crystallography; hit MW ≪ HTS but ligand efficiency higher. Vemurafenib (Zelboraf, Roche/Plexxikon 2011) — BRAF V600E inhibitor for melanoma — traced to a 7-azaindole fragment.

Virtual screening / structure-based. Schrödinger Glide, OpenEye Omega/FRED/ROCS, AutoDock Vina (Trott-Olson 2010), GOLD (CCDC), MOE (Chemical Computing Group). Ultra-large library docking: Lyu, Wang, Tolmachova, Shoichet 2019 Nature (~170 million compounds via Enamine REAL space; D4 and AmpC hits). Free-energy perturbation (FEP+; Schrödinger) for absolute and relative binding affinities; OpenMM/OpenFF for open-source.

ASMS — affinity selection mass spectrometry. HitGen, WuXi AppTec; size-exclusion or photo-cross-linking, then LC-MS readout.

Phenotypic screening. Whole-cell or zebrafish assays without molecular target a priori; resurgent post-2010 (Swinney-Anthony 2011 NRDD — “How were new medicines discovered?” — historical analysis showing phenotypic dominance pre-1990).

Lead optimization rules

Lipinski Rule of Five (Lipinski, Lombardo, Dominy, Feeney 1997 Adv Drug Deliv Rev — at Pfizer): orally bioavailable small molecules typically have MW < 500 Da, cLogP < 5, hydrogen-bond donors ≤ 5, hydrogen-bond acceptors ≤ 10. Roughly 90% of marketed oral drugs satisfy ≥ 3 of the four. Kinase inhibitors and macrocycles push boundaries; modern beyond-rule-of-five (bRo5) chemistry is explicit territory for PROTACs and oral peptides.

Veber rules (Veber, Johnson et al. 2002 GSK): rotatable bonds ≤ 10, polar surface area ≤ 140 Ų for oral bioavailability.

QED — quantitative estimate of drug-likeness (Bickerton, Paolini, Besnard, Muresan, Hopkins 2012 Nat Chem — “Quantifying the chemical beauty of drugs”) — a weighted desirability function combining MW, ALogP, HBD, HBA, PSA, RotB, aromatic rings, structural alerts.

Ligand efficiency LE = −1.4 × log(IC50) / heavy atom count; lipophilic ligand efficiency LLE = pIC50 − cLogP. Both used routinely in fragment-to-lead progression.

DMPK — drug metabolism and pharmacokinetics

ADME (absorption, distribution, metabolism, excretion) governs oral bioavailability F%, half-life t½, clearance CL, volume of distribution V_d, and ultimately dose and dosing schedule. Cytochrome P450 enzymes dominate phase I metabolism — CYP3A4 metabolizes ~50% of marketed drugs, with CYP2D6, CYP2C9, CYP2C19, CYP1A2 covering most of the remainder. P-glycoprotein (MDR1, ABCB1) efflux limits intestinal absorption and CNS penetration. First-pass hepatic metabolism after oral dosing reduces systemic exposure.

PK-PD modeling links concentration to effect; PBPK (physiologically based pharmacokinetic) models — Simcyp (Certara), GastroPlus (Simulations Plus), PK-Sim (Bayer/Open Systems Pharmacology) — combine organ-level physiology with compound properties. Allometric scaling extrapolates rodent and dog PK to human first dose.

Hit-to-lead chemistry toolkit

Bioisosteres (Patani, LaVoie 1996 Chem Rev — “Bioisosterism: a rational approach in drug design”). Classical: −CH2− ↔ −O− ↔ −NH−; tetrazole ↔ carboxylic acid; trifluoromethyl ↔ chlorine; phenyl ↔ thiophene; pyridine ↔ benzene. Modern scaffold hopping (Schneider, Roche): replace central scaffold to escape IP or improve properties; tools include SHAFTS, ROCS, BROOD.

Fragment growing / linking / merging in FBDD.

Kinase inhibitor design. Type I bind active DFG-in conformation (imatinib partially Type II); Type II bind DFG-out / inactive (sorafenib, imatinib at Bcr-Abl); Type III allosteric outside ATP pocket; Type IV substrate-competitive bivalent. Hinge-region H-bonding (Met-gatekeeper interaction) is the canonical anchor. Covalent kinase inhibitors target Cys (BTK ibrutinib at C481; EGFR osimertinib at C797; KRAS G12C sotorasib).

Macrocycles and beyond-rule-of-five

Cyclization improves PK, selectivity, and conformational pre-organization. Pioneered analytically by Veber’s somatostatin work; modern enabling chemistries include ring-closing metathesis (Grubbs catalysts), copper-free azide–alkyne click, and amide coupling. Computational tools: Schrödinger PathFinder, MacroModel; Sun lab (Stanford) machine-learning permeability prediction. Companies: Polyphor (Allschwil; PEG-modified macrocyclic peptides), Bicycle Therapeutics (Cambridge UK; bicyclic peptides via TATA scaffold; BT8009 BT5528 in oncology), Pepscan, Versant-backed cyclic peptide platforms.

PROTACs — proteolysis targeting chimeras

Crews lab (Yale) introduced the concept in 2001 (Sakamoto et al. 2001 PNAS — “Protacs: chimeric molecules that target proteins to the SCF complex for ubiquitination and degradation”). Bivalent molecule: target-binding ligand + linker + E3-ligase recruiter. Cereblon (CRBN) and Von Hippel-Lindau (VHL) E3 ligases dominate; recently IAP, MDM2, KEAP1, DCAF15 explored. Clinical leaders:

  • ARV-471 / vepdegestrant (Arvinas–Pfizer): ER PROTAC in Phase 3 (VERITAC-2) for ER+/HER2− breast cancer.
  • KT-474 (Kymera–Sanofi): IRAK4 degrader Phase 2 atopic dermatitis and hidradenitis suppurativa.
  • ARV-110 / bavdegalutamide: AR PROTAC mCRPC.
  • NX-2127 (Nurix): BTK degrader CLL.

Molecular glues are a related, monovalent class — thalidomide / lenalidomide / pomalidomide were retrospectively recognized as CRBN molecular glues degrading IKZF1/3, CK1α, GSPT1. The IMiD class anchors Bristol Myers Squibb / Celgene multiple myeloma franchise. Mereo BioPharma, Monte Rosa Therapeutics, C4 Therapeutics, Foghorn, Plexium pursue de novo glue discovery.

Adjacent modalities: RIPTACs (regulator-induced proximity targeting chimeras), LYTACs (lysosome-targeting chimeras; Bertozzi lab Stanford for extracellular and membrane targets via mannose-6-phosphate or ASGPR), AUTACs (autophagy-targeting chimeras), and antibody–drug conjugates (ADCs) which share the bivalent / payload-delivery logic.

Covalent drugs

Targeted covalent inhibitors (TCIs) exploit a non-catalytic nucleophile (typically cysteine) near the active site. Warheads in marketed drugs: acrylamide (ibrutinib BTK at C481; afatinib EGFR at C797; osimertinib EGFR at C797; acalabrutinib BTK), α,β-unsaturated carbonyl, vinylsulfonamide, chloroacetamide, fluorosulfate, sulfonyl fluoride. KRAS G12C inhibitors sotorasib (Lumakras, Amgen 2021) and adagrasib (Krazati, Mirati 2022) bind the cysteine in the switch-II pocket of the inactive GDP-bound state — landmark “drugging the undruggable” advance based on Shokat lab (UCSF) original disclosure (Ostrem 2013 Nature). Nirmatrelvir (Paxlovid component, Pfizer) is a covalent SARS-CoV-2 Mpro inhibitor via nitrile warhead.

Beyond-small-molecule modalities

  • Oral peptides. Semaglutide (Rybelsus, Novo Nordisk 2019; first oral GLP-1 agonist; formulated with SNAC absorption enhancer co-developed with Emisphere). Ozempic / Wegovy injectable forms; total Novo franchise USD 21 billion 2023. Tirzepatide (Mounjaro / Zepbound, Lilly; GIP/GLP-1 dual). Octreotide oral (Mycapssa, Chiasma/Amryt). Linaclotide (Linzess, Ironwood/Allergan) GC-C agonist.
  • siRNA conjugates. GalNAc-conjugated siRNA delivers to hepatocytes via ASGPR. Alnylam franchise: Givlaari (givosiran, 2019, AHP), Oxlumo (lumasiran, 2020, PH1), Amvuttra / Onpattro (vutrisiran / patisiran, ATTR amyloidosis), Wainua (eplontersen, with Ionis; ATTRv-PN, 2023). Inclisiran (Leqvio, Novartis/Alnylam; PCSK9; chronic LDL-C; twice-yearly dose) — landmark cardiovascular application.
  • LNP-mRNA. mRNA-1273 (Spikevax, Moderna) and BNT162b2 (Comirnaty, Pfizer-BioNTech). Patisiran (Onpattro, Alnylam 2018) was the first siRNA drug licensed and the first LNP nucleic-acid drug. Cross-link to virology-and-vaccine-platforms for mRNA vaccine details.
  • ASOs — antisense oligonucleotides. Nusinersen (Spinraza, Ionis/Biogen) SMA via SMN2 splice switching; Golodirsen (Vyondys 53, Sarepta) DMD exon-skipping; Mipomersen (Kynamro, withdrawn); Tofersen (Qalsody, Biogen/Ionis 2023) SOD1 ALS.

Top medicinal chemistry assets

Blockbuster small-molecule and antibody franchises 2023:

  • Keytruda (pembrolizumab, Merck; anti-PD1) — USD 25 B.
  • Ozempic + Wegovy + Rybelsus (semaglutide, Novo Nordisk) — USD 21 B combined.
  • Humira (adalimumab, AbbVie; anti-TNF-α) — USD 14 B (declining post-LOE 2023).
  • Eliquis (apixaban, BMS/Pfizer; Factor Xa) — USD 19 B.
  • Comirnaty + Spikevax (COVID mRNA) — declining.
  • Mounjaro / Zepbound (tirzepatide, Lilly) — rapidly growing.
  • Lecanemab (Leqembi, Eisai/Biogen 2023) — first disease-modifying anti-amyloid mAb in Alzheimer’s; pricing ~USD 26k/yr pre-insurance.

Part II — Photochemistry

Foundations of photoexcitation

Absorption of a photon promotes a molecule from the ground singlet S0 to an excited singlet Sn → relaxes by internal conversion (IC) to S1 (Kasha’s rule: emission from lowest excited state of given multiplicity). From S1: fluorescence (radiative, 10⁻⁹ s typical) → S0; intersystem crossing (ISC, spin-forbidden but enabled by spin-orbit coupling) → T1; from T1 phosphorescence (10⁻⁶ – 10² s) → S0. Non-radiative pathways include IC, ISC, photochemistry (bond-breaking, photo-isomerization, electron transfer). Jablonski diagram (Jablonski 1933) is the canonical schematic.

Selection rules: ΔS = 0 for spin-allowed transitions; spin-orbit coupling (heavy atoms — Ir, Ru, Pt — and certain elements with low-lying triplet states; El-Sayed’s rules govern ISC rate) determine ISC efficiency.

Quantum yield Φ = (molecules undergoing the process) / (photons absorbed). Sum over all S1 fates equals 1: Φ_F + Φ_P + Φ_IC + Φ_ISC + Φ_rxn = 1. Beer–Lambert law A = ε c L (molar absorption coefficient ε in M⁻¹ cm⁻¹, typically 10² – 10⁵ for organic chromophores; allowed π–πtransitions higher than forbidden n–π).

Photoredox catalysis

The renaissance of organic photochemistry (post-2008) driven by visible-light absorbing transition-metal polypyridyl complexes [Ru(bpy)3]²⁺ and fac-Ir(ppy)3, organic photocatalysts (4CzIPN — 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene; Mes-Acr+ N-methyl mesityl acridinium of Fukuzumi 2004; Eosin Y; Rose Bengal; perylene; phenothiazines). Three seminal 2008-09 papers established the visible-light era:

  • Nicewicz and MacMillan 2008 Science — “Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes” — Ru(bpy)3²⁺ + chiral amine SOMO catalysis.
  • Ischay, Anzovino, Du, Yoon 2008 JACS — Ru-catalyzed intramolecular [2+2] of bis(enones).
  • Narayanam, Tucker, Stephenson 2009 JACS — Ru-catalyzed reductive dehalogenation.

Subsequent milestones include MacMillan–Doyle 2014 Science — Ni/photoredox dual catalysis for Csp³–Csp³ cross-coupling; Knowles enabling electrocatalysis (Princeton; PCET); Glorius EDA exciplex photochemistry (Münster); Melchiorre asymmetric photochemistry (ICIQ Tarragona); Gianetti electro-photo dual; List enamine catalysis. Photoredox is now a mainstream medicinal-chemistry tool — sp³-rich late-stage functionalization, decarboxylative coupling (Baran, MacMillan).

Mechanism families: single-electron transfer (SET) generating radical cations / anions; energy transfer (EnT — sensitization of triplets, alkene Z/E isomerization, [2+2] cycloaddition via triplet); HAT — hydrogen atom transfer using quinuclidine, decatungstate, or thiol catalysts.

Photochemical reactions

  • Pericyclic — [2+2] cycloaddition. Paterno-Büchi (1909/1954) carbonyl + alkene → oxetane via triplet diradical. Standard alkene [2+2] is photochemically allowed (suprafacial-suprafacial) but thermally forbidden under Woodward-Hoffmann selection rules.
  • Norrish reactions. Norrish I (α-cleavage of ketone → acyl + alkyl radicals; aliphatic ketones). Norrish II (γ-H abstraction → 1,4-biradical → either Yang cyclization to cyclobutanol or fragmentation to enol + alkene).
  • Di-π-methane rearrangement (Zimmerman 1966; Iowa State / UWisconsin).
  • Electrocyclic. Woodward-Hoffmann selection rules flip between thermal (conrotatory ↔ disrotatory) and photochemical regimes — 6π thermal disrotatory, photochemical conrotatory.
  • HAT photocatalysis for sp³ C–H functionalization (MacMillan decatungstate, quinuclidine-based; Knowles thiol catalysis; Doyle).
  • Carbene and nitrene generation via diazo, diazirine, azide precursors; diazirine is the dominant photoaffinity warhead in chemical biology (Brunner 1980).
  • Decarboxylative coupling. Acridinium / Ir-photoredox + Ni for sp³ amino-acid-derived radicals to aryl halides (MacMillan, Doyle 2014–onward).
  • EDA — electron-donor-acceptor exciplex photochemistry. Pre-formed ground-state complexes absorbing visible light without external photocatalyst; Glorius, Melchiorre 2017+.
  • Diels-Alder photo (radical-anion). Photoredox-activated formal Diels-Alder via radical cation cycloaddition (Yoon, Nicewicz).
  • Photoclick reactions. 2,5-diaryl tetrazole UV/visible-light generates nitrile imine 1,3-dipole → [3+2] with alkenes (Lin lab 2008 JACS); photo-IEDDA inverse-electron-demand Diels-Alder.

Photocatalysis for energy and fuels

Water splitting. Fujishima-Honda 1972 Nature — TiO2 photoanode (n-type rutile) splits water under UV with bias. Thermodynamic threshold 1.23 V (4 e⁻ overall; OER kinetics demand much higher overpotential).

  • Domen lab (Tokyo / Shinshu): SrTiO3:Al, Rh-Cr2O3 cocatalyst — 0.76% solar-to-hydrogen (STH) over 100 m² panel array, 2021 Nature; visible-light absorber search ongoing — Ta3N5, BaTaO2N, SnNb2O6.
  • BiVO4 + WO3 photoanodes for OER half.
  • Tandem GaN/Si — record laboratory STH ~30%; PEC (photoelectrochemical) cells vs PV-electrolyzer split debate.

CO2 reduction. Photo + electro shared mechanisms; Cu generates hydrocarbons (CH4, C2H4, ethanol; Tang Bao Hori 1985+), Ag/Au selectively to CO, Sn / Bi to formate. Molecular photo-CO2 catalysts: Re(bpy)(CO)3X (Lehn 1983), Ru-pyridyl, Mn(bpy)(CO)3Br, Fe-porphyrin. MOFs UiO-66, MIL-101, COFs as light-harvesting + catalysis platforms (Lin Chicago, Yaghi UC Berkeley).

N2 fixation. Photochemical and electrochemical N2 reduction to NH3 still elusive at meaningful Faradaic efficiency and current density; controversies around contamination (Andersen-Chorkendorff 2019 Nature on rigorous protocols).

Photo-protecting groups

PPGs (“caged” compounds) release biological actives or reagents on UV / visible photolysis. Workhorses: o-nitrobenzyl (1966 Barltrop; widely used in caged ATP, neurotransmitters), nitrophenylethyl (NPE), coumarin-4-yl-methyl (e.g., DMNB / DMCM coumarins), BODIPY-based PPGs (Winter, Bender, Klán; visible-light-cleavable). Critical for spatial-temporal control in cell biology (caged Ca²⁺, glutamate, IP3) and chemistry (photoacid generators in lithography).

Photodynamic therapy

PDT employs a photosensitizer that, on illumination, generates singlet oxygen ¹O2 by Type II energy transfer (or radicals via Type I) to kill local tumor cells or pathogens. Hematoporphyrin derivative (Photofrin, Axcan; first FDA-approved 1995 for esophageal cancer). 5-aminolevulinic acid pro-drug (Levulan, DUSA; Ameluz, Biofrontera) — endogenous protoporphyrin IX accumulation in dysplastic tissue; topical for actinic keratosis. Verteporfin (Visudyne, Bausch + Lomb / QLT) for AMD wet form. Foscan (temoporfin, Biolitec) head/neck. Methylene blue (used in PCT for plasma viral inactivation). Antimicrobial PDT for biofilm control.

Photobiology

  • Vision. Rhodopsin = opsin + 11-cis retinal (vitamin A aldehyde); photon-induced cis-trans isomerization to all-trans is the only photochemical step in the visual cascade (Wald, Hubbard 1958; Wald 1967 Nobel).
  • Circadian photoreception. Melanopsin (OPN4) intrinsically photosensitive retinal ganglion cells; suppresses melatonin under short-wavelength light.
  • Photosynthesis. Z-scheme — PSII (P680) → PQ → cyt b6f → PC → PSI (P700) → Fd → FNR → NADPH. Calvin-Benson cycle fixes CO2. See cell-molecular-biology for compartmentalization details.
  • UV damage and repair. UVB induces CPD (cyclobutane pyrimidine dimer) and 6-4 photoproducts in DNA; NER (nucleotide excision repair) is the canonical removal pathway; XP (xeroderma pigmentosum) — defective NER → severe sunlight sensitivity, skin cancer; mechanism elucidated by Sancar (2015 Chemistry Nobel with Lindahl, Modrich).
  • Vitamin D. UVB (290-315 nm) converts 7-dehydrocholesterol in skin → previtamin D3 → vitamin D3; hydroxylated in liver and kidney to 1,25(OH)2D3.

Single-molecule fluorescence and super-resolution

Cross-reference structural-biology. STED (Hell), PALM (Betzig), STORM (Zhuang) — Nobel 2014 Chemistry. SOFI, MINFLUX (Hell 2017 — sub-nm precision with structured illumination). FRET — Förster resonance energy transfer for nm-scale distance measurement; smFRET widely used for conformational dynamics. FCS — fluorescence correlation spectroscopy for diffusion and binding kinetics in solution and live cells.

Optogenetics

Microbial opsins co-opted for neural control. Channelrhodopsin-2 (ChR2) from Chlamydomonas reinhardtii — light-gated cation channel; Deisseroth, Boyden, Nagel 2005 Nat Neurosci — “Millisecond-timescale, genetically targeted optical control of neural activity.” Halorhodopsin (NpHR) — light-driven Cl⁻ pump for silencing. ArchT — H⁺ pump silencer. SOUL (Hwang) — improved kinetics. Step-function opsins (SFO) for prolonged effect. Chemogenetics (DREADDs — designer receptors exclusively activated by designer drugs; Roth UNC) is the parallel pharmacological-control approach using CNO / DCZ ligands. Cross-link proteomics-metabolomics-and-computational-neuroscience for the comp-neuro applications.

Spectroscopy

  • TCSPC — time-correlated single-photon counting. Picosecond–nanosecond fluorescence lifetimes; PicoQuant, Becker-Hickl, Edinburgh Instruments.
  • LIF — laser-induced fluorescence. Combustion, atmospheric chemistry (OH detection; field studies in atmospheric-chemistry-and-radiative-transfer).
  • Femtosecond pump-probe / transient absorption. Ultrafast dynamics 100 fs – ns; Ti:sapphire amplifier + WLC supercontinuum probe; Helios (Ultrafast Systems), Light Conversion; Nobel 1999 Zewail femtochemistry.
  • 2D electronic spectroscopy. Fleming, Engel — photosynthetic energy transfer; vibrational coherence debate.
  • SECM — scanning electrochemical microscopy. Local redox imaging at electrode interfaces.
  • Time-resolved X-ray — XFEL pump-probe (LCLS, European XFEL, SwissFEL); structural changes on fs-ps; Cammarata, Schreck.

Photochemistry meets medicinal chemistry

Photoredox cross-coupling now standard in mid-stage medicinal chemistry: late-stage Csp³ functionalization, deuterium incorporation (HAT D-source), photoredox amination, decarboxylative coupling, isotope labeling for ADME tracer studies. Photoaffinity probes — diazirine (Schreiber, Cravatt) or benzophenone — capture transient target interactions for chemoproteomic target ID. Photo-uncaging in vivo (BODIPY visible-light PPGs in tumor microenvironment; theranostic). PDT-immune-checkpoint combinations entering clinical trials 2024-25.

Adjacent

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