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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

New Derivatives of Bacteriopurpurin with Thiolated Au (I) Complexes: Dual Darkand Light Activated Antitumor Potency

Author(s): Mikhail A. Grin*, Sergei I. Tikhonov, Albina S. Petrova, Victor A. Pogorilyy, Аlexey N. Noev, Victor V. Tatarskiy, Dmitry B. Shpakovsky, Elena R. Milaeva, Elena V. Kalinina, Nikolai N. Chernov, Аlexander А. Shtil, Andrey F. Mironov, Andrey D. Kaprin and Elena V. Filonenko

Volume 20, Issue 1, 2020

Page: [49 - 58] Pages: 10

DOI: 10.2174/1871520619666190801102617

Price: $65

Abstract

Background: Conventional antitumor Photosensitizers (PS) are normally low toxic in the dark whereas light activation triggers massive cell death (photodynamic therapy, PDT).

Objective: To expand the therapeutic potential of PS to dual potency cytocidal agents, taking advantage of the use of bacteriopurpurin for a deeper tissue penetration of light, and suitability of the tetrapyrrolic macrocycle for chemical modifications at its periphery.

Methods: Conjugation of a pro-oxidant thiolate Au (I) moiety to the bacteriopurpurin core and evaluation of cytotoxicity in cell culture and in vivo.

Results: New water-soluble derivatives showed micromolar cytotoxicity for cultured human tumor cell lines in the dark, including the subline with an altered drug response due to p53 inactivation. Cellular PDT with the selected conjugate, thiolate Au (I)-dipropoxybacteriopurpurinimide (compound 6) with two triphenylphosphine Au fragments, triggered rapid (within minutes) cell death. Damage to the plasma membrane (necrosis) was a hallmark of cell death by compound 6 both in the dark and upon light activation. Furthermore, one single i.v. injection of compound 6 caused retardation of transplanted syngeneic tumors at the tolerable dose. Illumination of tumors that accumulated compound 6 significantly synergized with the effect of 6 in the dark.

Conclusion: Complexes of virtually non-toxic, photoactivatable bacteriopurpurin with the gold-containing organic moiety are considered the dual potency antitumor agents, tentatively applicable for intractable tumors.

Keywords: Bacteriopurpurin, Au (I) thiolates, photosensitizers, photodynamic therapy, photonecrosis, tumor cells.

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