Erwin von Angerer

Aroyl hydrazones of 2-phenylindole-3-carbaldehydes as novel antimitotic agents

Cell cycle arrest of malignant cells is an important option for cancer treatment. In this study, we modified the structure of antimitotic 2-phenylindole-3-carbaldehydes by condensation with hydrazides of various benzoic and pyridine carboxylic acids. The resulting hydrazones inhibited the growth of MDA-MB 231 and MCF-7 breast cancer cells with IC(50) values of 20-30 nM for the most potent derivatives. These 2-phenylindole derivatives also exerted an inhibitory effect on the growth of both proliferating and resting U-373 MG glioblastoma cells. Though the hydrazones exhibited similar structure-activity relationships as the aldehydes, they did not inhibit tubulin polymerization as the aldehydes but were capable of blocking the cell cycle in G(2)/M phase. The cell cycle arrest was accompanied by apoptosis as demonstrated by the activation of caspase-3. Since these 2-phenylindole-based hydrazones display no structural similarity with other antitumor drugs they are interesting candidates for further development.

The inhibitory effect of 5-acetoxy-2-(4-acetoxyphenyl)-1-ethyl-3-methylindole (D 16726) on estrogen-dependent mammary tumors

The antineoplastic activity of the antiestrogen 5-acetoxy-2-(4-acetoxyphenyl)-1-ethyl-3-methylindole (D 16726) was determined in several estrogen-dependent mammary tumor models. The growth of the DMBA-induced rat mammary carcinoma was inhibited by doses ranging from 1 to 12 mg/kg. The maximum decrease of tumor area was 67% (control + 635%). D 16726 was also active against MNU-induced rat mammary tumors and transplanted MXT tumors of the mouse. The growth of estrogen receptor-positive MCF-7 breast cancer cells was inhibited by the hydroxy derivative D 15414 (10(-8)-10(-5) M). Because of the high binding affinity of D 15414 for the estrogen receptor (RBA 6.7-10.0) and the lack of activity against hormone-independent MDA-MB 231 breast cancer cells, a specific mode of action involving the estrogen receptor is likely.

Sulfate derivatives of 2-phenylindols as novel steroid sulfatase inhibitors : an in vitro study on structure-activity-relationship

The growth of hormone-dependent mammary tumor cells is stimulated by non-conjugated estrogens. One important source of these hormones in the tumors could be the enzymatic hydrolysis of circulating estrogen sulfates by steroid sulfatase (EC 3.1.6.2). Inhibition of this enzyme may result in reduced levels of endogenous estrogens and, consequently, in a reduced proliferation rate of estrogen-dependent tumors. This paper reports on a series of inhibitors of steroid sulfatase based on sulfated derivatives of 2-phenylindoles, a new class of mammary tumor inhibiting compounds. Starting from hydroxy-substituted 2-phenylindoles, a number of mono- and disulfates were synthesized and tested for steroid sulfatase inhibiting properties. The enzymatic test was based on the measurement of [3H]estrone formed from [3H]estrone sulfate in the presence of various amounts of inhibitor. The concentrations which result in a 50% reduction of the rate of hydrolysis (IC50) were determined. Sulfates of hydroxylated 2-phenylindoles are substrates of steroid sulfatase. The most potent of these inhibitors show affinities which are comparable to the affinities of natural substrates. The test data further suggest that monosulfated compounds exhibit stronger enzyme-inhibiting properties than do disulfates.

Antitumor activity of antiestrogenic phenylindoles on experimental prostate tumors

Two antiestrogenic phenylindoles (D 16726 and D 15413) were tested for their prostatic tumor-inhibiting activity. Both compounds exerted a strong inhibitory effect on prostate and seminal vesicle weight of intact rats and mice comparable to that of diethylstilbestrol. Their estrogenic properties, however, are much lower than those of DES. Therefore, there is no direct correlation between estrogenic potency and inhibition of accessory sex organ weights. The tumor-inhibiting activity of D 16726 and D 15413 on the androgen-dependent R 3327 Dunning prostatic carcinoma and the human prostatic tumor PC 82 implanted in nude mice equals that of castration or of diethylstilbestrol. Both 2-phenylindoles had good affinities for estrogen receptors from calf uterine and R 3327 tumor cytosol, but no affinities for androgen and progesterone receptors. As these 2-phenylindoles have much lower estrogenic properties than diethylstilbestrol, they may also have low side-effects, and can therefore be of interest for the therapy of the prostatic carcinoma.

The tumor-inhibiting effect of isomeric dichloro(diphenylethylenediamine)platinum(II) complexes.

SummaryRing unsubstituted dichloro(diphenylethylenediamine)platinum(II) complexes show a dependence of their antitumor activity on the configuration and position of phenyl rings in ethylenediamine ligand. Dichloro(1,1-diphenylethylenediamine)platinum(II) (1d) and meso-dichloro(1,2-diphenylethylenediamine)-platinum(II) (meso-2d) have a weaker effect on the human breast-cancer cell line MDA-MB 231 and on rat leukemia L5222 than (±)-dichloro(1,2-diphenylethylenediamine)platinum(II) ((+)-2d) and its enantiomers (+)-2d and (-)-2d which cause marked and comparable inhibition of both tumors; (±)-2d is also active on ADJ/PC 6 plasmacytoma of the mouse and on cisplatin-, daunomycin-, and cisplatin/daunomycin-resistant Ehrlich ascites tumors of the mouse. The differences in activity of the diastereomers (±)-2d and meso-2d, for which distinct influences on the DNA secondary structure can be demonstrated CD spectroscopically may be explained by a steric hindrance of the drug-DNA interaction.

2,5-Diphenylfuran-based pure antiestrogens with selectivity for the estrogen receptor α ☆

The estrogen receptor alpha (ERalpha) is understood to play an important role in the progression of breast cancer. Therefore, pure antiestrogens with a preference for this receptor form are of interest as new agents for the treatment of this malignancy. Several chemical structures with selective binding affinity for ERalpha have been identified and might be useful for the synthesis of ERalpha-selective pure antiestrogens. In this study we applied the 2,5-diphenylfuran system which is closely related to the triphenylfurans described by others. Various side chains with amino and/or sulfur functions were linked to C3 to convert the furans to estrogen antagonists without residual estrogenic activity. The degree of alpha-selectivity which ranges from 2.5- to 236-fold is strongly influenced by the alkyl group at C4. Antiestrogenic potency was determined in MCF-7/2a breast cancer cells stably transfected with a luciferase gene under the control of an ERE. The 2,5-bis(4-hydroxyphenyl)furan with an ethyl substituent and a 6-[N-methyl-N-(3-pentylthiopropyl)amino]hexyl side chain exerted the strongest antiestrogenic effect in this series with an IC(50) value of 50 nM in cells stimulated with 1 nM estradiol. The RBA values of this derivative were 18% (ERalpha) and 3.4% (ERbeta) of estradiol, respectively. It inhibited the growth of wild-type MCF-7 cells with an IC(50) value of 22 nM. The data show that the 2,5-diphenylfuran system is appropriate for the development of pure antiestrogens with preference for ERalpha.

Sulfamoyloxy-substituted 2-phenylindoles: Antiestrogen-based inhibitors of the steroid sulfatase in human breast cancer cells

Estrone sulfate (E1S) is an endogenous prodrug that delivers estrone and, subsequently, estradiol to the target cells following the hydrolysis by the enzyme estrone sulfatase which is active in various tissues including hormone dependent breast cancer cells. Blockade of this enzyme should reduce the estrogen level in breast cancer cells and prevent hormonal growth stimulation. Sulfamates of a variety of phenolic compounds have been shown to be inhibitors of estrone sulfatase. Our rational is based on findings that these inhibitors can undergo hydrolysis and the pharmacological effects of the free hydroxy compounds contribute to the bioactivity of the sulfamates. A desirable action of the metabolites would be an estrogen antagonism to block stimulatory effects of residual amounts of estrogens. Thus, we synthesized a number of sulfamoyloxy-substituted 2-phenylindoles with side chains at the indole nitrogen that guarantee antiestrogenic activity. All of the new sulfamates were studied for their inhibitory effects on the enzyme estrone sulfatase from human breast cancer cells and their (anti)hormonal activities in stably transfected human MCF-7/2a mammary carcinoma cells. The hormonal profile of the sulfamates was partly reflected by the properties of the corresponding hydroxy precursors. Some of the sulfamoylated antiestrogens strongly inhibited estrone sulfatase activity with IC(50) values in the submicromolar range. They were devoid of agonist activity and suppressed estrone sulfate-stimulated gene expression mainly by blocking the enzyme. Examples are the disulfamates of the indoles ZK 119, 010 and ZK 164, 015. Their IC(50)s for sulfatase inhibition were 0.3 and 0.2 microM, respectively, and 50 and 80 nM, respectively, for the inhibition of E1S-stimulated luciferase expression in transfected MCF-7 cells. With some of the new sulfamates an additional direct antiestrogenic effect was noticed which might be due to a partial hydrolysis during incubation and would improve the growth inhibitory effect on estrogen-sensitive breast cancer cells.

2-Phenylindole sulfamates: inhibitors of steroid sulfatase with antiproliferative activity in MCF-7 breast cancer cells

A number of 2-phenylindole sulfamates with lipophilic side chains in 1- or 5-position of the indole were synthesized and evaluated as steroid sulfatase (estrone sulfatase) inhibitors. Most of the new sulfamates inhibited the enzymatic hydrolysis of estrone sulfate in MDA-MB 231 breast cancer cells with IC(50) values between 2 nM and 1 microM. A favorable position for a long side chain is the nitrogen of a carbamoyl group at C-5 of the indole when the phenyl ring carries the sulfamate function. These derivatives inhibit gene activation in estrogen receptor (ER)-positive MCF-7 breast cancer cells in submicromolar concentrations and reduce cell proliferation with IC(50) values of ca. 1 microM. All of the potent inhibitors were devoid of estrogenic activity and have the potential for in vivo application as steroid sulfatase inhibitors.

New inhibitors of tubulin polymerisation

Despite the relatively long tradition of the vinca alkaloids in cancer chemotherapy, the spectrum of compounds with the same mode of action has until recently been quite small. It was mainly the discovery of paclitaxel (Taxol®, Bristol-Myers Squibb) that stimulated the search for novel substances of natural or synthetic origin that interact with tubulin and microtubules. Since the vinca structure allowed only minor alterations and the potencies of colchicine and combretastatin derivatives were rather low, most of the industrial activities concerned two new, highly-active classes of natural products, the dolastatins and the cryptophycins. Cemadotin, like other dolastatins, inhibits the growth of various tumour cells in nanomolar concentrations and is currently undergoing Phase II clinical studies. Even more active are the cryptophycins with IC50 values in the picomolar range. One of the interesting features of cryptophycin 52 (LY 355703), which is now in clinical trials, is its high activity in multi-drug ...

Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines.

Bicalutamide is a non‐steroidal anti‐androgen commonly used in the treatment of prostate carcinoma. We analysed the transcriptional response to bicalutamide treatment with the aim of explaining the inhibition of telomerase in the androgen‐sensitive cell line LNCaP and the effects of bicalutamide on the androgen‐insensitive cell line DU145. Cells treated with 80 μm bicalutamide in steroid‐depleted medium for 1 day were analysed in duplicate by Affymetrix Human Genome Focus Arrays. Response to bicalutamide in LNCaP cells was represented by downregulation of androgen‐regulated genes, activation of the p53 pathway and inhibition of telomerase, which was associated with downregulation of v‐myc avian myelocytomatosis viral oncogene homologue (MYC) and telomerase reverse transcriptase subunit. In DU145 cells we observed the influence of cell density on bicalutamide effectivity such that highly confluent cells showed lesser sensitivity than low confluent ones. In conclusion, we provide an explanation for telomerase inhibition after androgen receptor blockade in LNCaP cells and we also report activation of the p53 pathway in LNCaP cells and in‐vitro sensitivity to bicalutamide of low confluent androgen‐insensitive DU145 cells. These findings might have implications for both experimental and clinical research into prostate cancer. In particular, activation of the p53 pathway after treatment with 80 μm bicalutamide could justify usage of bicalutamide dosages higher than 150 mg daily in androgen‐sensitive carcinoma therapy.