Synthesis of Thio-lignan Analogues, Bioequivalent Salvinal without Unfavored Aldehyde.
J Org Chem
; 86(10): 7092-7106, 2021 05 21.
Article
in En
| MEDLINE
| ID: mdl-33979157
ABSTRACT
The oxygen in the benzofuran (BF) of three antiproliferative natural neolignans, salvinal (1), obovaten (2), and 2-[7-methoxy-2-(4-methoxyphenyl)-3-methylbenzofuran-5-yl]ethanol (3), was replaced with sulfur to form the new biological scaffold benzothiophene (BT) thio-lignans 4-6. Compounds 1-6 and 18 synthesized derivatives were evaluated for antiproliferative activity against five human cancer cell lines, including a multidrug-resistant cell line. Thio-salvinal (4) displayed significant antiproliferative effects with half-maximal inhibitory concentration (IC50) values of 0.57-0.95 µM against all tested cell lines, except for the HER2 negative breast cancer cell line MCF-7. This thio-lignan was 6.5-9.4 times more potent than parent 1. However, the related thio-lignans, 5 and 6, showed much weaker antiproliferative effects than 4 and were less potent than the parent natural benzofuran lignans 2 and 3. Newly synthesized thio-lignan 33 affected cell cycle progression at 24 and 48 h in the G2/M transition and S phase, respectively, as well as promoted sub-G1 induction by stimulating microtubule depolymerization and nuclear fragmentation. Since a highly reactive aldehyde in salvinal is generally not appropriate for drug development, we have successfully found nonaldehyde derivative 33 showing biological activity similar to salvinal by replacing BF with BT and an aldehyde with 1,3-dioxolane.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Benzofurans
/
Lignans
/
Antineoplastic Agents
Limits:
Humans
Language:
En
Journal:
J Org Chem
Year:
2021
Document type:
Article
Affiliation country:
Japan