90
D.C. Hill et al.
dose-dependent manner. It ws concluded that the compounds were estrogen
agonists. In addition, BE-14348B only inhibited progesterone-receptor binding
weakly, showed little cytotoxicity against MCF-7 and Hela cells, and had low
toxicity in vivo.
Napyradiomycins A and B1 were isolated from a Streptomyces sp. during
a screening programme for estrogen-receptor antagonists [62]. They are
quinone antibiotics which had previously been isolated from Chainia rubra [63].
Napyradiomycins A and B1 inhibited estrogen-receptor binding in a dose
dependent manner, and were less potent than tamoxifen. Napyradiomycin B1
was an estrogen-receptor antagonist, as determined by effects on growth of
estrogen stimulated MCF-7 cells. It reduced estrogen-induced increase in rat
uterus carcinoma slightly but significantly. Tamoxifen and napyradiomycin did
not show dose dependent inhibition in vivo, suggesting that they exhibited
partial estrogen-receptor agonistic activity.
R1128 A, B, C and D were discovered during the same screening programme.
They are alkylated anthraquinones which were isolated from a Streptomyces sp.
[64]. These compounds were less potent than tamoxifen in the receptor-binding
assay, and had weak cytotoxicity against human lung adenocarcinoma A459
cells, human adenocarcinoma MCF-7 cells, mouse lymphocytic leukaemia P388
cells and mouse bone marrow cells. R1128B had very low toxicity in mice and
rats. Based on experiments measuring the colony formation of MCF-7 cells in
soft agar, the R1128 compounds were concluded to be estrogen-receptor antagonists.
Androgen is also known to play an important role in cancer, being active in
benign prostatic hyperplasia and prostate cancer. A receptor binding assay
based on the binding of [-3H]-mibolerone to rat prostate cytosol, and separating
the bound from the free ligand by centrifugation with dextran coated charcoal,
was used in the isolation and identification of WB2838 from a Pseudomonas sp.
[65]. Triamicinolone acetonide was present in the reaction mixture to inhibit
ligand binding to progesterone and glucocorticoid-receptors. WB2838 is
a chlorinated phenol-substituted pyrrole which was discovered using this assay,
and had been isolated and identified previously as an antifungal antibiotic [66].
WB2838 inhibited androgen binding to its receptor in a dose dependent manner,
and was more potent than flutamide, but less potent than chlormadinone
acetate (CMA), two known androgen-receptor antagonists. The compound was
a competitive inhibitor of androgen-receptor binding, and only weakly inhibited
estrogen-receptor binding. In addition, WB2838 had characteristics of an androgen-receptor antagonist, and a weak partial agonist, as determined by effects on
androgen-responsive mouse mammary carcinoma SC3 cells in vitro. Oral administration of WB2838 reduced testosterone-induced weight increases in rat
ventral prostate and seminal vesicle slightly but significantly.
WS9761A and B, anthracene derivatives produced by a Streptomyces sp.,
were identified as androgen receptor antagonists during the same screening
programme [67]. WS9761A and B were competitive inhibitors of androgenreceptor binding. The compounds inhibited binding in a dose dependent
D.C. Hill et al.
dose-dependent manner. It ws concluded that the compounds were estrogen
agonists. In addition, BE-14348B only inhibited progesterone-receptor binding
weakly, showed little cytotoxicity against MCF-7 and Hela cells, and had low
toxicity in vivo.
Napyradiomycins A and B1 were isolated from a Streptomyces sp. during
a screening programme for estrogen-receptor antagonists [62]. They are
quinone antibiotics which had previously been isolated from Chainia rubra [63].
Napyradiomycins A and B1 inhibited estrogen-receptor binding in a dose
dependent manner, and were less potent than tamoxifen. Napyradiomycin B1
was an estrogen-receptor antagonist, as determined by effects on growth of
estrogen stimulated MCF-7 cells. It reduced estrogen-induced increase in rat
uterus carcinoma slightly but significantly. Tamoxifen and napyradiomycin did
not show dose dependent inhibition in vivo, suggesting that they exhibited
partial estrogen-receptor agonistic activity.
R1128 A, B, C and D were discovered during the same screening programme.
They are alkylated anthraquinones which were isolated from a Streptomyces sp.
[64]. These compounds were less potent than tamoxifen in the receptor-binding
assay, and had weak cytotoxicity against human lung adenocarcinoma A459
cells, human adenocarcinoma MCF-7 cells, mouse lymphocytic leukaemia P388
cells and mouse bone marrow cells. R1128B had very low toxicity in mice and
rats. Based on experiments measuring the colony formation of MCF-7 cells in
soft agar, the R1128 compounds were concluded to be estrogen-receptor antagonists.
Androgen is also known to play an important role in cancer, being active in
benign prostatic hyperplasia and prostate cancer. A receptor binding assay
based on the binding of [-3H]-mibolerone to rat prostate cytosol, and separating
the bound from the free ligand by centrifugation with dextran coated charcoal,
was used in the isolation and identification of WB2838 from a Pseudomonas sp.
[65]. Triamicinolone acetonide was present in the reaction mixture to inhibit
ligand binding to progesterone and glucocorticoid-receptors. WB2838 is
a chlorinated phenol-substituted pyrrole which was discovered using this assay,
and had been isolated and identified previously as an antifungal antibiotic [66].
WB2838 inhibited androgen binding to its receptor in a dose dependent manner,
and was more potent than flutamide, but less potent than chlormadinone
acetate (CMA), two known androgen-receptor antagonists. The compound was
a competitive inhibitor of androgen-receptor binding, and only weakly inhibited
estrogen-receptor binding. In addition, WB2838 had characteristics of an androgen-receptor antagonist, and a weak partial agonist, as determined by effects on
androgen-responsive mouse mammary carcinoma SC3 cells in vitro. Oral administration of WB2838 reduced testosterone-induced weight increases in rat
ventral prostate and seminal vesicle slightly but significantly.
WS9761A and B, anthracene derivatives produced by a Streptomyces sp.,
were identified as androgen receptor antagonists during the same screening
programme [67]. WS9761A and B were competitive inhibitors of androgenreceptor binding. The compounds inhibited binding in a dose dependent