Towards lead compounds as anti-cancer agents via new phaeosphaeride A derivatives

Victoria V Abzianidze; Sofya A Zakharenkova; Natalia I Moiseeva; Petr P Beltyukov; Valeriy A Polukeev; Yaroslav A Dubrovskii; Victor A Kuznetsov; Yuri G Trishin; Jennifer E Mejia; Alvin A Holder

doi:10.1016/j.bmcl.2018.11.003

Towards lead compounds as anti-cancer agents via new phaeosphaeride A derivatives

Bioorg Med Chem Lett. 2019 Jan 1;29(1):59-61. doi: 10.1016/j.bmcl.2018.11.003. Epub 2018 Nov 9.

Affiliations

¹ Research Institute of Hygiene, Occupational Pathology and Human Ecology, Federal Medical Biological Agency, p/o Kuz'molovsky, Saint Petersburg 188663, Russian Federation. Electronic address: vvaavv@mail.ru.
² Saint Petersburg State University of Industrial Technologies and Design, Saint Petersburg 198095, Russian Federation.
³ N.N. Blokchin National Medical Research Center of Oncology, Moscow 115478, Russian Federation.
⁴ Research Institute of Hygiene, Occupational Pathology and Human Ecology, Federal Medical Biological Agency, p/o Kuz'molovsky, Saint Petersburg 188663, Russian Federation.
⁵ Institute of Experimental Medicine, Saint Petersburg 197376, Russian Federation.
⁶ Research Institute of Hygiene, Occupational Pathology and Human Ecology, Federal Medical Biological Agency, p/o Kuz'molovsky, Saint Petersburg 188663, Russian Federation; Saint Petersburg State University, Institute of Chemistry, Saint Petersburg 198504, Russian Federation.
⁷ Department of Chemistry and Biochemistry, Old Dominion University, 4541 Hampton Boulevard, Norfolk, VA 23529, United States.
⁸ Department of Chemistry and Biochemistry, Old Dominion University, 4541 Hampton Boulevard, Norfolk, VA 23529, United States. Electronic address: aholder@odu.edu.

PMID: 30447888
DOI: 10.1016/j.bmcl.2018.11.003

Abstract

New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor studies were carried out on the U937, HCT-116, PC3, MCF-7, A549, К562, NCI-H929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 (IC₅₀ = 0.59 ± 0.27 µM) was observed to be 11 times more active than PPA (IC₅₀ = 6.5 ± 0.30 µM) towards the NCI-H929 cell line, with a therapeutic index of 18. Compound 6 was determined to be over half and 16 times more active than etoposide towards the NCI-H929 (IC₅₀ = 0.9 ± 0.05 µM) and A549 (IC₅₀ = 100 ± 7.0 µM) cell lines, respectively.

Keywords: Anti-cancer agents; Etoposide; HCT-116 cell line; HEF cell line; In vitro studies; Mercapto derivative; Natural products; Phaeosphaeride A; Therapeutic index.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Cell Line
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Bridged Bicyclo Compounds, Heterocyclic
phaeosphaeride A