Developing Chlorin/Arylaminoquinazoline Conjugates with Nanomolar Activity for Targeted Photodynamic Therapy: Design, Synthesis, SAR, and Biological Evaluation

Developing Chlorin/Arylaminoquinazoline Conjugates with Nanomolar Activity for Targeted Photodynamic Therapy: Design, Synthesis, SAR, and Biological Evaluation Full article

Journal

Journal of Medicinal Chemistry
ISSN: 0022-2623 , E-ISSN: 1520-4804

Output data

Year: 2025, Volume: 68, Number: 2, Pages: 1901–1923 Pages count : DOI: 10.1021/acs.jmedchem.4c02643

Authors

Krylova Lubov V. ¹ , Otvagin Vasilii F. ¹ , Gribova Galina P. ¹ , Kuzmina Natalia S. ¹ , Fedotova Ekaterina A. ¹ , Zelepukin Ivan V. ² , Nyuchev Alexander V. ¹ , Kustov Andrey V. ³ , Morshnev Philipp K. ³ , Berezin Dmitry B. ⁴ , Koifman Mikhail O. ⁴ , Vatsadze Sergey Z. ⁵ , Balalaeva Irina V. ¹ , Fedorov Alexey Yu. ¹

Affiliations

1	Lobachevsky State University of Nizhny Novgorod, Gagarina av. 23, Nizhny Novgorod 603950, Russian Federation
2	Uppsala University, Dag Hammarskjölds väg, 20751 85 Uppsala, Sweden
3	G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, Ivanovo 153045, Russian Federation
4	Institute of Macroheterocyclic Compounds, Ivanovo State University of Chemistry and Technology, Ivanovo 153012, Russian Federation
5	N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prosp., Moscow 119991, Russian Federation

In this report, we developed novel chlorin/arylaminoquinazoline conjugates for targeted photodynamic therapy of cancer. The synthesized photosensitizers consisted of chlorin-e6 metallocomplexes (Zn, In, or Pd) conjugated with arylaminoquinazoline ligands with high affinity for epidermal growth factor receptors (EGFR). Additionally, the selectivity and antitumor properties of the conjugates were investigated in the EGFR-expressing A431 human tumor cell line in vitro. Among the tested molecules, the In-containing conjugate effectively inhibited tumor cell proliferation at nanomolar concentrations, a rare property for conventional photosensitizers. In in vivo experiments, the conjugates rapidly accumulated at the tumor site in nude mice bearing A431 xenograft tumors. Subsequent distribution analysis among different tissues was carried out using fluorescence imaging and elemental analysis. Finally, we demonstrated that the most promising In-containing conjugate was capable of inhibiting xenograft tumor growth in mice through combinational therapy. This therapeutic approach, combined with the conjugate’s confirmed safety profile, highlights its potential for effective and safe cancer treatment.

Krylova L.V. , Otvagin V.F. , Gribova G.P. , Kuzmina N.S. , Fedotova E.A. , Zelepukin I.V. , Nyuchev A.V. , Kustov A.V. , Morshnev P.K. , Berezin D.B. , Koifman M.O. , Vatsadze S.Z. , Balalaeva I.V. , Fedorov A.Y.
Developing Chlorin/Arylaminoquinazoline Conjugates with Nanomolar Activity for Targeted Photodynamic Therapy: Design, Synthesis, SAR, and Biological Evaluation
Journal of Medicinal Chemistry. 2025. V.68. N2. P.1901–1923. DOI: 10.1021/acs.jmedchem.4c02643 WOS OpenAlex

Web of science:	WOS:001388714000001
OpenAlex:	W4405997840

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