Synthesis and Antitumor Activity of Methoxy‐indolo[2,1‐a]isoquinolines

Abstract

Methoxy-indolo[2,l-a]isoquinolines 8a-f and their dihydroderivatives 7a-f were synthesized by Bischler-Napieralski reaction of the (bromomethoxyphenyl)-[2-(methoxyphenyl)-ethyl]acetamides 4a-f, reduction, subsequent cyclization and dehydrogenation. They were tested for cytostatic activity in vitro using P388 D x leukemia and MDA MB 231 mammary tumor cells. The trimethoxy-5,6-dihydroindoloisoquinoline 7d and the tetramethoxyindoloisoquinoline 8f showed an inhibition of cellproliferation of about 70 % at a concentration of 10" 5 molar. The aim of our investigations is the synthesis of cytostatic compounds with binding affinity for the estrogen receptor, that can be used for the selective treatment of hormone dependent mammary tumors. Suitable structures for this approach are tetracyclic N-heterocycles, which are known to intercalate into the DNA 1 ) and are able to bind to the estrogen receptor 2 ).Based on these findings, we synthesized a number of indolo[2,l-a]isoquinolines 8a-f and their dihydro analogues 7a-f. Cytostatic activity of these compounds was evaluated in vitro using MDA-MB 231 mammary tumor cells and P388 D 1 leukemia cells. ChemistryThe synthesis was performed as outlined in scheme 1. The starting methyl bromophenylacetates 2a-c were synthesized by bromination of the corresponding phenylacetic acids and conversion to the methyl esters. The 2-phenylethylamine 3a was obtained directly by LiAlH 4 reduction of the 3-methoxy-ß-nitrostyrene 3) or, in better yield, in two steps with NaBH 4 followed by LiAlH 4 . The best method was the hydrogenation of the 3-methoxy-phenylacetonitrile with Rh/C.The reaction of the bromo-phenylacetates 2a-c with the 2-phenylethylamines 3a and 3b afforded the corresponding amides 4a-f. Cyclisation to the 3,4-dihydroisoquinolines was accomplished by a modified Bischler-Napieralski method using POCl 3 in CH 3 CN. The crude products were treated with NaBH 4 to give the 1,2,3,4-tetrahydro-l-benzylisoquinolines 5a-f. In the case of 4c (2-Bromo-4,5-dimethoxyphenyl)-(3,4-dihydro-6-methoxyisoquinolyl-l)-ketone was formed as a byproduct, probably by air oxidation 4) . The correct substitution pattern in the isoquinoline ring was confirmed by ^-NMR spectroscopy.The benzylisoquinolines 5a-f were converted into the tetracyclic indolo[2,l-a]isoquinolines by treatment with NaH in DMSO. This reaction must involve a benzyne intermediate 5) because both bromo compounds 5a and 5b led to the same structure. The reaction mixture contained two products

Three-component coupling reactions of isoquinolines, dimethyl acetylenedicarboxylate and indoles: a facile synthesis of 3-indolyl-1,2-dihydro-2-isoquinolinyl-2-butenedioate

“…4 They are known to exhibit various biological activities such as antileukaemic, 5 tubulin polymerization inhibitory 6 and anti-tumour activities. 7,8 Related synthetic acetoxy-substituted 5,6-dihydro[2,1-a]isoquinolines (iii) also exhibit strong binding affinities for the oestrogen receptor of MDA-MB 231 and MCF-7 mammary tumour cell lines. 9 It has also been reported that hydroxy-substituted indolo-[2,1-a]isoquinolines bind to the colchicine binding site and inhibit the polymerization of tubulin.…”

Simple and one-pot synthesis of new heterocyclic compounds in three-component reactions between isoquinoline or phenanthridine and acetylenic esters in the presence of N-heterocycles or 1,3-dicarbonyl compounds

“…25 They are known to exhibit various biological activities [26][27][28][29][30][31][32][33][34] such as antileukaemic, 35 tubulin polymerization inhibitory 36 and anti-tumour activities. 37 As previously reported, 38 reaction between phenanthridine and two mol equivalents of dimethyl acetylenedicarboxylate, leads to the…”

C‐12‐Substituted Indolo[2,1‐a]Isoquinolines as Estrogen Receptor Affinic Cytostatic Agents

“…Compounds 2f and 4f were dehydrogenated to the aromatic indolo[2,l-a]isoquinoiines 5 and 6 using Pd/C. For [1][2][3][4] R the determination of the binding affinities of 2b, 4b and 4f for the ER, the methoxy groups were cleaved by BBr 3 . The resulting phenols were converted to the acetates 7, 8, and 9, because of their better stability.…”