Design, Synthesis, and Biological Evaluation of Ellipticine−Estradiol Conjugates

Abstract

Three ellipticine-estradiol conjugates were synthesized in an effort to target the cytotoxicity of ellipticine to estrogen-receptor positive cells. The three conjugates were prepared with linker chains extending from the 17 alpha position of the estradiol to N-2 (compound 3), N-6 (compound 4), and C-9 (compound 5) positions of ellipticine. The ellipticine-estradiol conjugates were evaluated for their abilities to bind to estrogen receptors, to inhibit topoisomerase II, and for their cytotoxicities in human cancer cell lines. Conjugates 3 and 5 displayed weak binding affinities of 0.132 and 0.303 for the estrogen receptor (relative to estradiol = 100), while conjugate 4 did not show any detectable binding to the estrogen receptor. Compound 3 was a moderate inhibitor of topoisomerase II (IC50 24.1 microM), while 4 and 5 were inactive. Conjugate 3 was consistently more cytotoxic (GI50 values 1-10 microM) than compounds 4 and 5 (GI50 values 10-100 microM) in a variety of human cancer cell lines. None of the compounds displayed any selectivity for estrogen-receptor positive cell lines, which probably reflects their weak affinities for estrogen receptors.

Novel Conversion of 4-Aminoquinolines to New Tricyclic (<i>R,S</i>)-3-Methylazeto[3,2-<i>c</i>] Quinolin-2(2a<i>H</i>)-Ones and Versatile One Step Synthesis of <i>N</i>-(Quinolin-4-yl) Carbamates from 4-Aminoquinolines

“…The H-3 proton appeared at the aromatic proton region likely due to the highly deshielding effect of the neighboring carbonyl and imine functions. In addition, the long range 1 H- 13 C correlations (HMBC, Fig. 2) of H-3/H-4, H-3/H-4a, H-3/C-9, H-3/C-2, H-11/C-3, and H-11/C-9 supported that 1-azetinone ring is incorporated with the quinoline ring in 21a.…”

“…1 H NMR and 13 C NMR spectra were recorded on a 600 MHz, Brucker AVANCE 600 DRX and 400 MHz, Brucker Top-Spin spectrometers in the indicated solvent. The chemical shifts were reported in ppm () relative to TMS.…”

“…1H, m, ArH), 8.30-8.32 (1H, m, ArH), 9.98 (1H, s, exchangeable, NH). 13 C NMR (DMSO-d 6 ) δ 10.4, 22.0, 25.4, 66.6, 110.9, 119.3, 122.4, 125.0, 128.8, 129.4, 142.3, 148.4 …”

“…7,8 While reaction of 1 or 3,4,5-trichlorophenyl chloroformate with di-2-pyridylmethanol (12) resulted in the formation of 5-(2′-pyridyl)pyrido[1,2-c]oxazol-2-one (13) via N-acylation followed by intramolecular cyclization. 13 On the other hand, Devraj et al 14 reported that reaction of naturally occurring anticancer ellipticine (14) with 1 followed by in situ reduction of the Nacylated intermediate gave 2-acyl-1,2-dihydroellipticine (15). Thus, the facileness of compound 1 was demonstrated by the formation of quaternary pyridinium cation with the heterocyclic nitrogen atom.…”

Antitumor Drug Ellipticine Inhibits the Activities of Rat Hepatic Cytochromes P450

“…Ellipticine and its more soluble derivatives (9-hydroxyellipticine, 9-hydroxy-N 2 -methylellipticinium, 9-chloro-N 2 -methylellipticinium and 9-methoxy-N 2 -methylellipticinium) exhibit promising results in the treatment of osteolytic breast cancer metastases, kidney sarcoma, tumors of brain and myeloblastic leukemia (for summary see 1 ). In order to increase the selectivity of ellipticine antitumor drugs, the attempts to link them to specific vectors able to direct these drugs towards target cells, were performed [2][3][4] . One such conjugate, a heptagastrin fragment linked to ellipticine via a spacer has recently been synthesized and shown to be selectively taken up and to be cytotoxic to cells expressing the cholecystokinin type B receptor 4 .…”