Design, synthesis, and bioactivity study on Lissodendrins B derivatives as PARP1 inhibitor

Design, Synthesis, and Biological Evaluation of Marine Lissodendrins B Analogues as Modulators of ABCB1-Mediated Multidrug Resistance

“…A series of Lissodendrins B analogues was designed, in which the 2-positions of 1-methyl-1 H -imidazole rings were substituted with different functional groups. The key intermediates 7 and 8 were prepared and reported by our groups previously [ 19 , 31 ], as depicted in Scheme S1 . Based on the structural characteristics of marine products and the third-generation ABCB1 inhibitors, the numbers of the methoxy group of the C ring, dimethoxy-substituted tetrahydroisoquinoline fragment, benzene rings and the different linkers between the imidazole ring and B ring were the key groups to improve the reversal resistance activity, and the typical moieties were synthesized as follows.…”

“…The key intermediate 21 was synthesized using the method depicted in Scheme S4 . The key intermediate 21 was prepared and reported by our groups previously [ 31 ]. Compound 20 was prepared from the starting material 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride refluxed in the mixture of CH 3 CN with methyl bromoacetate and potassium carbonate for 8 h. Then, compound 20 with lithium hydroxide in the mixture of THF and H 2 O gave the corresponding lithium carboxylate, which was protonated with hydrochloric acid to generate key intermediate 21 .…”

“…As shown in Scheme 1 , the target products could be synthesized through the acylation reaction of compound 7 or 8 with different methoxy-substituted benzoyl acid and tetrahydroisoquinoline derivatives. The compounds A 1 – A 2 , B 1 – B 2 , C 1 – C 2 , D 1 – D 2 , and E 1 – E 5 were prepared and reported by our groups previously [ 31 ]. Compound 7 or 8 was coupled with compound 14 or 25 to yield, respectively, D 4 and E 6 , catalyzed by EDCI and HOAt in CH 2 Cl 2 .…”

“…Successive oxidation of A 1 , B 1 , C 1 , and D 1 with mercuric nitrate hydrate (2 equiv) gave α -diketones compounds A 3 , B 3 , C 3 , and D 3 , respectively. The compounds A 3 , B 3 , C 3 , and D 3 were prepared and reported by our groups previously [ 31 ].…”

“…Compound 7 or 8 was coupled with compound 14 or 25 to yield, respectively, D4 and E6, catalyzed by EDCI and HOAt in CH2Cl2. were prepared and reported by our groups previously [31]. For the identification of effective ABCB1 inhibitors, we evaluated the drug resistance reversal effects of these newly synthesized compounds, using DOX-resistant K562/ADR and MCF-7/ADR cells as screening models.…”