2-fluorocordycepin: chemoenzymatic synthesis and study of anticancer activities in vitro

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Abstract

Two methods for obtaining 2-fluorocordycepin were proposed and implemented: chemical synthesis from 2-fluoroadenosine with a yield of 34% and chemical-enzymatic synthesis with a yield of 66%, including the production of 3-deoxyerythropentofuranose-1-phosphate and subsequent transglycosylation using E. coli purine nucleoside phosphorylase. The cytotoxic activity of 2-fluorocordycepin in vitro was assessed. It was shown that 2-fluorocordycepin exhibits an anti-metabolic effect on a number of tumor cell lines (Jurkat, Raji, MCF-7, THP-1, U937, A549, LS174T), which allows us to consider this compound as a promising candidate for the development of antitumor drugs.

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A. O. Arnautova

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS; Engelhardt Institute of Molecular Biology RAS

Author for correspondence.
Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997; ul. Vavilova 32, Moscow, 119991

K. V. Antonov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

E. A. Zorina

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

М. A. Simonova

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

A. S. Paramonov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

О. S. Zhukova

N.N. Blokhin National Medical Research Center of Oncology

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Kosigina 4/1, Moscow, 119334

M. V. Kiselevskiy

N.N. Blokhin National Medical Research Center of Oncology

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Kosigina 4/1, Moscow, 119334

А. L. Kayushin

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

I. V. Fateev

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

Е. V. Dorofeeva

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

B. Z. Eletskaya

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

М. Ya. Berzina

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

О. S. Smirnova

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

Т. V. Egorova

Moscow Pedagogical State University

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Malaya Pirogovskaya 1/1, Moscow, 119991

R. S. Esipov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

А. I. Miroshnikov

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

I. D. Konstantinova

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry RAS

Email: arnautova_ibch@mail.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

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Supplementary files

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2. Fig. 1. Adenosine, cordycepin and 2-fluorocordycepin.

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3. Fig. 2. Scheme of the transglycosylation reaction of 2-F-Ado and 3-dIno in the synthesis of 2-fluorocordycepin.

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4. Fig. 3. Scheme of synthesis of 2-F-3-dAdo, where (a) – α-acetoxyisobutyryl bromide/MeCN, (b) – H2/Pd, (c) – NH3, CH3OH.

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5. Fig. 4. Scheme of the synthesis of compound (VI), where (a) – H2SO4, acetone, H2O, (b) – toluoyl chloride, pyridine, (c) – thiocarbonyldiimidazole, DMAP, MeCN, (d) – dimethyl phosphite, benzoyl peroxide, dioxane, (e) – acetic acid, water, (f) – acetyl bromide, acetic anhydride, dioxane, H3PO4, (g) – H3PO4, Bu3N, (h) – LiOH, H2O.

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6. Rice. 5. Scheme for the synthesis of 2-F-3-dAdo.

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7. Fig. 6. Dynamics of nucleoside (IV) accumulation depending on the ratio of 2-F-Ado to 1-P-3-dRib.

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8. Fig. 7. Dependence of the conversion of 2-F-Ado into compound (IV) (168 h) on the pH value of potassium phosphate buffer.

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9. Fig. 8. Dependence of the conversion of 2-F-Ado into compound (IV) (120 h) on the temperature of the reaction mixture.

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10. Fig. 9. Dependence of the conversion of 2-F-Ado to compound (IV) (120 h) on the concentration of PNP.

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11. Fig. 10. Dynamics of accumulation of 2-F-3-dAdo.

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12. Fig. 11. Curves of the dependence of cell survival of different lines on the concentrations of 2-F-3-dAdo and 3-dAdo.

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