Original article Synthesis, cytostatic evaluation and structure activity relationships of novel bis-indolylmethanes and their corresponding tetrahydroindolocarbazoles Mardia T. El Sayed a, b, * , Khadiga M. Ahmed c , Kazem Mahmoud a , Andreas Hilgeroth a a Institute of Pharmacy, Martin-Luther University, Research Group of Drug Development and Analysis, Wolfgang- Langenbeck-Straße 4, 06120 Halle, Saale, Germany b Applied Organic Chemistry Department, National Research Centre, Cairo, Egypt c Natural Compounds Laboratory, National Research Centre, Cairo, Egypt article info Article history: Received 5 September 2014 Received in revised form 2 November 2014 Accepted 5 December 2014 Available online 11 December 2014 Keywords: Bis-indolylmethanes Tetrahydroindolo[2,3-b]carbazoles One dose screening Five dose screening Antipoliferative activity Nanomolar scale abstract BIMs (bis-indolylmethanes) (1 aen ) were synthesized using glacial acetic acid as a protic acid for pro- motion of the condensation reaction of indoles with aldehydes in high yields (86e98 %). Corresponding tetrahydroindolo[2,3-b]carbazoles (2 aem ) were synthesized via condensation of BIMs with aldehydes. Ten synthesized compounds have been submitted to the national cancer institute in the USA where all the submitted samples have been selected for one dose screening. As a result of the one dose screening of BIMs (1 e,f,h,i,n ) and of the indolocarbazoles (2 e,f,h,i,j ) the average highest cytostatic effects was recorded here for the BIM 1 h and the indolocarbazole (2 e ) that showed the lowest mean values of “47.39%” and of “21.63%” respectively. Both compounds (1 h and 2 e ) were further tested in five dose screening with the tested substance (1 h ) being significantly more sensitive for several cancers cell line as corresponding to their GI 50 values. Furthermore, the basically substituted derivative 2 e showed the highest antipoliferative activity in a nanomolar scale towards the three selected cancers cell lines Non small lung cell NCIeH460 with GI 50 “616 nM”, Ovarian Cancer cell line OVCAR-4 with GI 50 “562 nM” and Breast Cancer cell line MCF7 with GI 50 “930 nM”. © 2014 Elsevier Masson SAS. All rights reserved. 1. Introduction In recent years a considerable attention has been paid on the synthetic ways leading to indole derivatives because of their bio- logical activities. Various indole derivatives, such as 3-substituted indoles, are common components of drugs and are generally found to be of pharmaceutical interest in a variety of therapeutic areas [1]. In addition, 3-substituted indole derivatives are also versatile intermediates in organic synthesis [2], due to the feasi- bility of their 3-position for an electrophilic substitution. The electrophilic substitution reactions of indoles with aromatic alde- hydes afford corresponding BIMs. Several catalysts such as protic acids [3e6,31], Lewis acids [7e10], ionic liquids [11], and others are used to promote these reactions. The 3-position of indole is the preferred site for the electrophilic substitution reactions. A simple and direct method for the synthesis of 3-alkylated indole de- rivatives involves the condensation of indoles or its substituted derivatives with electrophilies (aldehydes or ketones or imines). Aldehydes either aliphatic or aromatic are the most important and widely used electrophiles in such reactions. Bisindolylalkane de- rivatives are found in bioactive metabolites of terrestrial and ma- rine origin. Recently, Maciejewska et al. [12] used DNA-based electrochemical biosensors to prove that bis(5-methoxyindol-3- yl)methane [13] considerably reduces the growth of cancer cell lines such as HOP-92 (lung), A498 (renal) and MDAMB-231/1TCC (breast) Their results also indicate that BIMs could potentially be applied as chemotherapeutic agents against tumours [14]. It has been reported that, DIM-C-p-PhC 6 H 5 substituted in the phenyl ring with a para-t-butyl, trifluoromethyl (DIM-C-p-PhCF 3 ) substituent and indole ring-substituted analogs are selective PPARg modulators [15] in several cancer cell lines with high antiproliferative activity [16e25]. Other study investigated the antileukaemic activity and molecular mechanisms of action of a newly synthesized ring- * Corresponding author. Institute of Pharmacy, Martin-Luther University, Research Group of Drug Development and Analysis, Wolfgang- Langenbeck-Straße 4, 06120 Halle, Saale, Germany. Applied Organic Chemistry Department, National Research Centre, Cairo, Egypt. E-mail address: mardia_elsayed2009@yahoo.com (M.T. El Sayed). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2014.12.008 0223-5234/© 2014 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 90 (2015) 845e859