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

Abstract

Methoxysubstituted 5,6-dihydro-indolo[2,l-a]isoquinolines with a methyl (2b-f) or a formyl group at C-12 (4a-f) and 12,12-dimethylisoquinolinium salts (3b-f) were synthesized and tested for cytostatic activity in vitro. The tetramethoxy-indoloisoquinoline 4f was the most active derivative in the P 388 Dl leukemia cell line, whereas compounds with two methoxy groups (4a, 4b) were more potent against the MDA-MB 231 mammary tumor cells. The tetraacetoxy-12-formyl-5,6-dihydro-indoloisoquinoline 9 has proven to be active in both cell lines (T/C = 5 %). In vivo it increased the life span of mice with P 388 leukemia (T/C = 133 %). The acetates 7 and 8 exhibited binding affinities for the estrogen receptor, but did not exert a selective action on hormone-dependent MCF-7 cells. In 12-Stellung substituierte Indolo[2,l-a]isochinoline als östrogenrezep-toraffine CytostatikaMethoxysubstituierte 5,6-Dihydro-indolo[2,l-a]isochinoline mit einer Methyl-(2b-f) oder Formylgruppe an C-12 (4a-f), sowie die 12,12-Dimethylisochinoliniumsalze 3b-f wurden synthetisiert und auf cytostatische Wirksamkeit in vitro getestet. Das Tetramethoxyindoloisochinolin 4f war die aktivste Substanz an P 388 D^Leukaemiezellen, während Verbindungen mit zwei Methoxygruppen (4a, 4b) an der menschlichen MD A-MB 231-Zellinie wirksamer waren. Das Tetraacetoxy-12-formyl-5,6-dihydroindoloisochinolin 9 war an beiden Zellinien aktiv (T/C = 5 %). In vitro verlängerte 9 die Überlebenszeit von Mäusen mit P 388-Leukaemie (T/C = 133 %). Die Acetate 7 und 8 zeigten Affinität zum Östrogenrezeptor, aber bewirkten keine selektive Hemmung an hormonabhängigen MCF-7 Zellen.In a previous paper we described the synthesis of a number of methoxysubstituted indolo[2,l-a]isoquinolines and their dihydro derivatives la-P). Their cytostatic activity was too low for the intended development of cytostatic agents binding to the estrogen receptor.Therefore, we tried to increase their activity by introduction of an additional substituent in position 12 of the tetracycle. Two different substituents were considered: the methyl group in order to increase the lipophilicity and a formyl group to decrease the electron density at the nitrogen. A further step was the conversion of the indoloisoquinolines to quaternary salts. All of the compounds were tested for their cytostatic activity in vitro using MDA-MB 231 mammary tumor cells and P 388 D x leukemia cells. Since a prerequisite for the binding to the estrogen receptor is the presence of hydroxy or acetoxy groups in the aromatic rings, the methoxy groups of some derivatives were cleaved. After conversion to the acetates, their binding affinities for the estrogen receptor (ER) were determined. ChemistryThe methoxy substituted 12-methyl-5,6-dihydro-indolo[2,l-alisoquinolines 2b-f were obtained by reacting lb-f 1}with an excess of CH 3 I at 90-93° in a sealed tube. Increasing the temp, to 110° led to the quaternary isoquinolinium salts 3b-f. The formation of quaternary N-methyl compounds can be ruled out by ^-NMR spectroscopy. The spectra showed ...

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.…”

Synthesis of indolo[2,1‐a]isoquinolines by CF3COOH‐induced cyclization

“…[ 1–5 ] Some of them have been shown to exhibit interesting biological activities [ 6‐12 ] including antileukemic and antitumor activities, [ 6‐8 ] nonsteroidal antiestrogen, [ 10 ] and anti‐tubulin activity. [ 11 ] Most of the reported methods for the synthesis of such alkaloids and related indolo[2,1‐ a ]isoquinolines [ 6‐59 ] involve the procedures ending up with the formation of the fused indole ring, such as benzyne method, [ 6–11 , 13–26 ] oxidative coupling, [ 27‐30 ] Bischler‐Napieralski cyclization, [ 31 ] photocyclization, [ 32 ] anionic cyclization, [ 33,34 ] radical cyclization, [ 34‐36 ] Pschorr cyclization, [ 37,38 ] Ni or Pd‐catalyzed intramolecular amination, [ 39,40 ] other metal‐catalyzed cycloaddition, [ 41‐50 ] and other methods. [ 12,51‐59 ] .…”

6‐Substituted Indolo[1,2‐c]quinazolines as New Antimicrobial Agents

“…In the latter category, indole derivatives carrying different substituents are associated with a wide range of biological activities including anticancer [12 -14], anticonvulsant [15], antimicrobial [16 -18], antimalarial [19,20], antiprotozoal [21], anti-inflammatory [22,23], and antiHIV [24] properties. Moreover, fused indole derivatives such as indolocarbazoles [25,26], indoloisoquinolines [27,28], indoloquinoxalines [29,30], indoloquinazolines [31 -33] display a number of interesting pharmacological properties. Based on the importance of these molecules, our attention was attracted towards the synthesis of new fused indole derivatives in order to find more potent biologically active molecules.…”