New transformations of phosphorylthioformic acid morpholides

Design and synthesis of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) as potent estrogen receptor alpha inhibitors: targeted treatment of hormone-dependent breast cancer cells

“…The synthetic route to the title Pho-STPYRs was based on our previous work. 31–34 Commercially available native hormones bearing an enolizable keto group were subjected to a two-step protocol, which involves (1) the Vilsmeier–Haack reaction providing chlorovinyl aldehydes and (2) the heterocyclization of the latter with phosphorylthioformic acid hydrazides via cascade electrocyclization/aromatization, giving 3′-phosphoryl-substituted steroidal pyridazines (Scheme 1). The reaction of 17-chloro-Δ 1,3,5(10),16 -estratrienes 3 and 4 , which were produced via chloroformylation of estrone methyl ester ( 1 ) and estrone ( 2 ), respectively, with phosphorylthioformic acid hydrazides 5 afforded D-ring annulated Δ 1,3,5(10) -estratrieno[16,17- d ]pyridazines 6–11 .…”

“…Cisplatin and 4-hydroxytamoxifen caused a 50% decrease in the viability of MCF7 cells at a concentration of about 6 μM. The activity of several synthesized steroids (6,30,31,33,34) was comparable with that of cisplatin and 4-hydroxytamoxifen. The highest activity against the MCF7 cells was observed for D-ring annulated pyridazines 33 and 34 of the androstane series containing the Δ 4 -3-keto moiety, which were chosen as lead compounds.…”

“…The synthetic route to the title Pho-STPYRs was based on our previous work. [31][32][33][34] Commercially available native hormones…”

“…3-Oxa-1′-(diphenylphosphine oxide)-4-androsteno [16,17-d] pyridazine (33). Obtained according to the general procedure from 52 mg of 3β-hydroxy-1′-diphenylphosphoryl-5androsteno [16,17-d] 3-Oxa-1′-(N,N′-diphenylphosphorylamido)-4androsteno [16,17-d]pyridazine (34). Obtained according to the general procedure from 55 mg of 3β-hydroxy-1′-(N,N′diphenylphosphorylamido)-5-androsteno [16,17-d] 3-Oxa-1′-(N,N′-di(tert-butyl)phosphorylamido)-4androsteno [16,17-d]pyridazine (35).…”