Steroids and Steroidases. XI. Synthetic Approaches to C-17 Bis(2-hydroxyethyl)-amino Compounds as Potential Precursors of 17-Hydroxyandrostane Nitrogen Mustards

Abstract

The synthesis of some potential nitrogen mustard precursor 17a-bis(2-hydroxyethyl)aminomethyl androst-l7a-01 derivatives has been achieved by two routes. During the investigation, unequivocal proof was obtained that addition of cyanide to 17-keto steroids gives predominantly 17a-hydroxy-l7a-cyano epimers.On rapporte la synthkse par deux voies difftrentes de quelques dtrivts de bis(hydroxy-2 tthyl) aminomkthyl-17a-androstol-17P qui sont possiblement actifs comme moutardes azotts. Au cours de ces travaux, on a pu obtenir des preuves sans tquivoques que I'addition du cyanure sur les 17-cetasttroldes conduit principalement aux tpimkres hydroxy-17P cyano-17a.Canadian Journal of Chemistry, 49, 2420 (1971) In the search for anti-tumor effective nitrogen mustards many compounds in which a steroid molecule has been used as a carrier for the bis(2-chloroethy1)amino group have been e~a m i n e d .~ We have previously synthesized and evaluated some androstane C-17 mustard compounds in which hormonally important ring A functional groups were present (2) and this communication describes our attempts to extend the investigation to androstane mustards in which both the ring A A4-3-keto and ring D 17P-hydroxyl functions of 17P-hydroxyandrost-4-en-3-one (testosterone) were retained.The compound selected as the initial target was the 17a-bis(2-chloroethy1)aminomethyl testosterone (la). The reservations expressed (2) regarding the usefulness of aliphatic nitrogen mustards in cancer chemotherapy owing to their high reactivity potential do not necessarily apply to hydroxy mustards of this type since for such compounds formation of a five-membered hydrogen bonded ring (3) should prolong the physiological activity by retarding the formation of the active ethylenimmonium ion species (4, 7-9).4 Our earlier studies (2) had indicated syntheses involving chlorination of bis(2-hydroxyethy1)-amino precursors in the final step to be the most satisfactory for the preparation of steroid mustards. Similar pathways to 2a were therefore examined and, as summarized in Schemes 1 and 3, two routes to the precursor trio1 2b proved satisfactory. In the cyanohydrin approach (Scheme l), 5a-androstan-17-one (3) was found to react smoothly with potassium cyanide in acetic acid to give in 87% yield a mixture of the C-17 cyanohydrin epimers in which the 17P-hydroxy compound 4 predominated to a large e~t e n t .~ Reduction of 4 with lithium aluminum hydride followed by reaction with ethylene oxide gave the 2-hydroxyethylamino compound 2b in 38% overall yield.The synthesis of the analogous bis(2-hydroxyethy1)amino precursor l b of androst-4-en-3-one was also achievable via cyanohydrin routes and the two pathways followed are outlined in Scheme 2. The sequence 6 -> 7 + 8 + 9 was explored first and although ketalization of testosterone (6) followed by Sarett oxidation of the C-17 hydroxyl group proceeded. smoothly to give the 17-keto-3-ketal 8 in good yield, the presence of the ketal function posed problems with regard to the subsequent C-17 cyanohydrination r...

Anabolic steroids detected in bodybuilding dietary supplements – a significant risk to public health

“…These data leads us to conclude the identity of the steroid component of supplement 8 as dihydro DMT (Figure 1(5)). [25] (See supplementary data for the NMR spectra, Figures S61-S65) …”

Steroid Conjugates as Potential Anti-Cancer Agents

“…Еще в середине XX в. была выдвинута гипотеза, что конъюгаты стероидов с известными лекарствами, в первую очередь с ДНК-алкилирующими агентами, могут с успехом использоваться для лечения гормонозависимых форм онкологических заболеваний, таких как рак молочной железы (РМЖ), предстательной железы, яичников, эндометрия и др. [23][24][25][26].…”

Man-Made Cytotoxic Steroids: Exemplary Agents for Cancer Therapy

“…In the same year (1971), another communication by Jones and Leman described the synthesis of some new androstane mustards in which both the ring A Δ 4 -3-keto and ring D 17β-hydroxyl functions of 17β-hydroxyandrost-4-en-3-one (testosterone) were retained; however, no reference to the biological activity was made …”