Synthesis of steroidal nitrosoureas with antitumor activity

Lam, Hiu Yung; Begleiter, Asher; Goldenberg, Gerald J.; Wong, Chiu-Ming

doi:10.1021/jm00188a015

Cited by 46 publications

(16 citation statements)

References 11 publications

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“…Wittig olefination of estrone benzyl ether, 23 followed by epoxidation with mCPBA gave the known 24 epoxide 1 as a mixture of diastereomers (Scheme 1). Deprotonation of 1 with lithium diisopropylamine, followed by cleavage of the benzyl ether under dissolving metal conditions gave the allylic alcohol 2 .…”

Section: Resultsmentioning

confidence: 99%

Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: A combined synthesis, binding and docking study

McCullough¹,

Neumann²,

Gone³

et al. 2014

Bioorganic & Medicinal Chemistry

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Various estrogen analogs were synthesized and tested for binding to human ERα using a fluorescence polarization displacement assay. Binding affinity and orientation were also predicted using docking calculations. Docking was able to accurately predict relative binding affinity and orientation for estradiol, but only if a tightly bound water molecule bridging Arg394/Glu353 is present. Di-hydroxyl compounds sometimes bind in two orientations, which are flipped in terms of relative positioning of their hydroxyl groups. Di-hydroxyl compounds were predicted to bind with their aliphatic hydroxyl group interacting with His524 in ERα. One nonsteroid-based dihdroxyl compound was 1000-fold specific for ERβ over ERα, and was also 25-fold specific for agonist ERβ versus antagonist activity. Docking predictions suggest this specificity may be due to interaction of the aliphatic hydroxyl with His475 in the agonist form of ERβ, versus with Thr299 in the antagonist form. But, the presence of this aliphatic hydroxyl is not required in all compounds, since mono-hydroxyl (phenolic) compounds bind ERα with high affinity, via hydroxyl hydrogen bonding interactions with the ERα Arg394/Glu353/water triad, and van der Waals interactions with the rest of the molecule.

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Section: Resultsmentioning

confidence: 99%

Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: A combined synthesis, binding and docking study

McCullough¹,

Neumann²,

Gone³

et al. 2014

Bioorganic & Medicinal Chemistry

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“…Compounds that reduced the growth of any one of the cell lines to 32% or less (negative numbers indicate cell kill) were termed as active and passed on for evaluation in the full panel of 60-cell lines over a 5-log dose range. Compounds 7,9,10,12,16, and 19 ± 21 were found to be active in this assay.…”

Section: )mentioning

confidence: 94%

“…Thus, modifications of steroids have been performed to produce agents like adrenocorticosteroids, progestins, estrogens, anti-estrogens, androgens, anti-androgens, and gonadotropin-releasing hormone analogs for the treatment of these cancers [9]. Certain steroidal nitrosoureas, e.g., 1 and 2, have been found to compete with estradiol for binding to cytosolic estrogen receptors in rat uterus [10] [11]. Compounds like 7-hydroxy-6-nitrocoumarin have shown selective antiproliferative activity by targeting p38 mitogen-activated protein kinase, a novel mechanism to inhibit renal cell carcinoma [12].…”

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confidence: 99%

Synthesis and in vitro Antineoplastic Evaluation of Certain 16‐(4‐Substituted Benzylidene) Derivatives of Androst‐5‐ene

Dubey

Piplani

Jindal

2004

Chemistry & Biodiversity

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In a systematic effort aimed at identifying new steroidal cytotoxic agents with potent antiproliferative activity against cancer cells, we synthesized certain 16‐[4‐(NO2, CN, and i‐Pr)substituted]benzylidene derivatives of androst‐5‐ene, 7–25, with pyrrolidino functionality in the 3β‐position of the steroid nucleus, i.e., 13–18 and 25. The selected compounds were examined for their cytotoxicity against a panel of three human cancer cell lines at the National Cancer Institute (NCI), Bethesda, USA. The results presented herein provide experimental evidence that compounds 7, 9, 10, 12, 16, and 19–21 induced apoptosis in human cancer cells.

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“…Compounds I±IV were synthesized by direct reaction between arylhydrazides and N-(2-chloroethyl)-N-nitrosocarbamoylazide (Lam et al 1979) and the detailed synthesis of these compounds has been described elsewhere (Gugova et al 1997). The newly obtained compounds were as follows: 4-(4-bromobenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamide (I), C 10 H 10 BrC1N 4 O 3 , M r 349.6; m.p.…”

Section: Chemistrymentioning

confidence: 99%

Genotoxic effect of 4-aroyl-1-(2-chloroethyl)- 1-nitrosohydrazinecarboxamides on Saccharomyces cerevisiae cells

Staleva¹,

Gugova²,

Venkov³

et al. 1998

Journal of Cancer Research and Clinical Oncology

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The study of some 4-aroyl-1-(2-chloroethyl)-1-nitrosohydrazinecarboxamides with a Saccharomyces cerevisiae mutagenicity test of increased sensitivity defined two of them, 4-(4-bromobenzoyl)-1-(2-chloroethyl)-1-nitrosohydrazinecarboxam ide and 4-(4-fluorophenyl)-1-(2-chloroethyl)-1-nitrosohydrazine carboxamide as typical cytostatic agents. At concentrations of 2-5 microg/ml the substances kill up to 60%-70% of cells without having any detectable recombinogenic and mutagenic effects. At the same concentrations, lomustine, well known as a cytostatic reference, demonstrated recombinogenic and mutagenic activity on yeast cells. The advantage of the newly synthesized substances is that, in a certain concentration range, their biological activity is mainly cytotoxic without induction of recombinogenic and mutagenic events in surviving cells.

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Synthesis of steroidal nitrosoureas with antitumor activity

Abstract: Four steroidal nitrosoureas with structures which may permit specific binding to estrogen receptor were synthesized. Inhibitory activity was observed against the growth of the DMBA-induced transplantable rat mammary tumor 13762.

Cited by 46 publications

References 11 publications

Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: A combined synthesis, binding and docking study

Probing the human estrogen receptor-α binding requirements for phenolic mono- and di-hydroxyl compounds: A combined synthesis, binding and docking study

Synthesis and in vitro Antineoplastic Evaluation of Certain 16‐(4‐Substituted Benzylidene) Derivatives of Androst‐5‐ene

Genotoxic effect of 4-aroyl-1-(2-chloroethyl)- 1-nitrosohydrazinecarboxamides on Saccharomyces cerevisiae cells

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