Amphenone B

Amphenone B

Clinical data
Other names	Amphenone; 3,3-bis(p-Aminophenyl)butan-2-one
Identifiers
IUPAC name 3,3-Bis(4-aminophenyl)butan-2-one
CAS Number	2686-47-7
PubChem CID	17591
ChemSpider	16631
UNII	Y2YUN941SL
KEGG	C07616
ChEBI	CHEBI:2678
CompTox Dashboard (EPA)	DTXSID70181370
Chemical and physical data
Formula	C16H18N2O
Molar mass	254.333 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC(=O)C(C)(C1=CC=C(C=C1)N)C2=CC=C(C=C2)N
InChI InChI=1S/C16H18N2O/c1-11(19)16(2,12-3-7-14(17)8-4-12)13-5-9-15(18)10-6-13/h3-10H,17-18H2,1-2H3 Key:MKBVGNJXUNEBAL-UHFFFAOYSA-N

Amphenone B, or simply amphenone, also known as 3,3-bis(p-aminophenyl)butan-2-one, is an inhibitor of steroid hormone and thyroid hormone biosynthesis which was never marketed but has been used as a tool in scientific research to study corticosteroids and the adrenal glands. ^{[1] [2]} It acts as competitive inhibitor of 11β-hydroxylase, 17α-hydroxylase, 17,20-lyase, 21-hydroxylase, and 3β-hydroxysteroid dehydrogenase, ^{[1] [2] [3]} as well as of cholesterol side-chain cleavage enzyme, ^{[4] [5]} thereby inhibiting the production of steroid hormones including glucocorticoids, mineralocorticoids, androgens, and estrogens. ^{[4] [6]} In addition, amphenone B inhibits the production of thyroxine by a thiouracil-like mechanism, specifically via inhibition of organic binding of iodine and uptake of iodide by the thyroid gland. ^{[7] [5] [8] [9]}

Amphenone B was first synthesized in 1950 and is a diphenylmethane derivative that was derived from the insecticide 2,2-di(p-chlorophenyl)-1,1-dichloroethane (p,p'-DDD), ^{[4] [10]} which in 1949 had been found to selectively induce adrenal atrophy. ^{[1] [11] [12]} In contrast to p,p'-DDD, which has direct cytotoxic effects on the adrenal glands via an unknown mechanism, ^[1] amphenone B does not have cytotoxic effects, and instead causes adrenal and thyroid gland hypertrophy due to respective inhibition of corticosteroid and thyroxine biosynthesis, subsequent loss of negative feedback on the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes, and consequent hypersecretion of adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH) from the pituitary gland. ^{[1] [2] [4]}

Amphenone B has also been found to produce progesterone-like progestogenic effects, including uterine hypertrophy and mammary lobuloalveolar development. ^{[1] [5] [13] [14]} These effects occurred even in animals that had been ovariectomized and hypophysectomized, suggesting that amphenone B might be acting directly on the target organs. ^{[1] [5]} However, it was found that adrenalectomy abolished the progesterone-like effects of amphenone B on the uterus, whereas those of progesterone were retained in the same experimental conditions, supporting the notion that amphenone B was not actually acting directly on the uterus. ^[1] Conversely, the progesterone-like effects of amphenone B on the mammary glands were found to persist even in adrenalectomized and ovariectomized animals. ^[5]

Amphenone B was tested in humans in the mid-1950s as a potential treatment for cortisol-dependent conditions such as Cushing's syndrome and adrenocortical carcinoma. ^{[1] [15]} In healthy subjects and patients with adrenocortical carcinoma, the drug was found to be effective in decreasing circulating levels of corticosteroids including cortisol, corticosterone, and aldosterone, ^[15] as well as in decreasing circulating levels of androgens and estrogens. ^{[1] [6]} Moreover, due to reduced aldosterone secretion, it caused marked diuresis and increased urinary sodium excretion. ^{[2] [13]} Unfortunately, amphenone B also caused many side effects, some severe, including drowsiness, gastrointestinal disturbances such as heartburn, nausea, and vomiting, morbilliform and pruritic rashes, methemoglobinemia, and hepatotoxicity including impaired liver function and hepatomegaly, ^[7] and these toxicities, as well as the diversity of its effects on various organs (e.g., also possessing antithyroid and even anesthetic activity), precluded its therapeutic use. ^{[2] [4] [11] [15] [13]}

Subsequently, analogues of amphenone B with reduced toxicity and improved specificity were developed. ^{[2] [4] [11]} One of the most potent of these was metyrapone (2-methyl-1,2-di(pyridin-3-yl)propan-1-one), ^[11] a selective inhibitor of 11β-hydroxylase, ^{[2] [6]} which was selected for clinical development and was eventually approved and marketed in 1958 as a diagnostic agent for Cushing's syndrome. ^{[1] [4] [16]} Another was mitotane (o,p'-DDD, or 1,1-(dichlorodiphenyl)-2,2-dichloroethane), an inhibitor of cholesterol side-chain cleavage enzyme and to a lesser extent of other steroidogenic enzymes, ^{[17] [18]} which additionally has selective and direct cytotoxic effects on the adrenal glands similarly to p,p'-DDD, and was introduced in 1960 for the treatment of adrenocortical carcinoma. ^[4] Aminoglutethimide (3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione), which was originally introduced as an anticonvulsant in 1960, is closely related structurally to amphenone B, ^{[4] [19]} and following its introduction, was found to cause adrenal insufficiency in patients due to inhibition of cholesterol side-chain cleavage enzyme and suppression of corticosteroid production. ^{[20] [21] [22]} The drug was subsequently repurposed for use in the treatment of metastatic breast cancer and Cushing's syndrome. ^{[20] [22]}

Amphenone B was originally thought to be 1,2-bis(p-aminophenyl)-2-methylpropan-1-one, but it was discovered in 1957 that the synthesis of amphenone B was accompanied by an unexpected molecular rearrangement and that the drug was actually 3,3-bis-(p-aminophenyl)butan-2-one. ^{[2] [13]} As such, early publications of amphenone B, and some subsequent publications, ^[5] refer to the drug by the incorrect structure. ^[2]

See also

• Steroidogenesis inhibitor

References

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3. Hiroshi I, Bun-Ichi T (April 1970). "Studies on enzyme reactions related to steroid biosynthesis: II. Submicrosomal distribution of the enzymes related to androgen production from pregnenolone and of the cytochrome P-450 in testicular gland of rat". Journal of Steroid Biochemistry. 1 (2): 83–6. doi:10.1016/0022-4731(70)90003-8.
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