TY - JOUR

T1 - Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction

AU - Данилкина, Наталья Александровна

AU - Хмелевская, Екатерина Алексеевна

AU - Ляпунова, Анна Геннадьевна

AU - Дьяченко, Александр Сергеевич

AU - Бунев, Александр Сиясатович

AU - Gasanov, Rovshan

AU - Гуреев, Максим Александрович

AU - Балова, Ирина Анатольевна

N1 - Publisher Copyright: © 2022 by the authors.

PY - 2022/9/17

Y1 - 2022/9/17

N2 - The scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final oxaenediyne was unstable under storage. Among the N-type Nicholas reactions, cyclization via an arenesulfonamide functional group followed by mild Co-deprotection was found to be the most promising, yielding 10-membered azaendiynes in high overall yields. By contrast, the Nicholas cyclization through the acylated nitrogen atom did not give the desired 10-membered cycle. It resulted in the formation of a pyrroline ring, whereas cyclization via an alkylated amino group resulted in a poor yield of the target 10-membered enediyne. The acylated 4-aminobenzenesulfonamide nucleophilic group was found to be the most convenient for the synthesis of functionalized 10-membered enediynes bearing a clickable function, such as a terminal triple bond. All the synthesized cyclic enediynes exhibited moderate activity against lung carcinoma NCI-H460 cells and had a minimal effect on lung epithelial-like WI-26 VA4 cells and are therefore promising compounds in the search for novel antitumor agents that can be converted into conjugates with tumor-targeting ligands.

AB - The scope and limitations of the Nicholas-type cyclization for the synthesis of 10-membered benzothiophene-fused heterocyclic enediynes with different functionalities were investigated. Although the Nicholas cyclization through oxygen could be carried out in the presence of an ester group, the final oxaenediyne was unstable under storage. Among the N-type Nicholas reactions, cyclization via an arenesulfonamide functional group followed by mild Co-deprotection was found to be the most promising, yielding 10-membered azaendiynes in high overall yields. By contrast, the Nicholas cyclization through the acylated nitrogen atom did not give the desired 10-membered cycle. It resulted in the formation of a pyrroline ring, whereas cyclization via an alkylated amino group resulted in a poor yield of the target 10-membered enediyne. The acylated 4-aminobenzenesulfonamide nucleophilic group was found to be the most convenient for the synthesis of functionalized 10-membered enediynes bearing a clickable function, such as a terminal triple bond. All the synthesized cyclic enediynes exhibited moderate activity against lung carcinoma NCI-H460 cells and had a minimal effect on lung epithelial-like WI-26 VA4 cells and are therefore promising compounds in the search for novel antitumor agents that can be converted into conjugates with tumor-targeting ligands.

KW - Bergman cyclization

KW - Nicholas reaction

KW - Sonogashira coupling

KW - alkynes

KW - benzenesulfonamides

KW - benzo[b]thiophene

KW - enediynes

KW - heterocycles

KW - Oxygen

KW - Enediynes

KW - Esters

KW - Nitrogen

KW - Sulfanilamide

KW - Cyclization

UR - http://www.scopus.com/inward/record.url?scp=85138440336&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/41851078-0360-34a6-9b48-863b29a2ce03/

U2 - 10.3390/molecules27186071

DO - 10.3390/molecules27186071

M3 - Article

C2 - 36144808

VL - 27

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 18

M1 - 6071

ER -