3,17-Disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol Derivatives:  Synthesis, In Vitro and In Vivo Anticancer Activity

Abstract

Estradiol-3,17-O,O-bis-sulfamates inhibit steroid sulfatase (STS), carbonic anhydrase (CA), and, when substituted at C-2, cancer cell proliferation and angiogenesis. C-2 Substitution and 17-sulfamate replacement of the estradiol-3,17-O,O-bis-sulfamates were explored with efficient and practical syntheses developed. Evaluation against human cancer cell lines revealed the 2-methyl derivative 27 (DU145 GI(50) = 0.38 microM) as the most active novel bis-sulfamate, while 2-ethyl-17-carbamate derivative 52 (GI(50) = 0.22 microM) proved most active of its series (cf. 2-ethylestradiol-3,17-O,O-bis-sulfamate 4 GI(50) = 0.21 microM). Larger C-2 substituents were deleterious to activity. 2-Methoxy-17-carbamate 50 was studied by X-ray crystallography and was surprisingly 13-fold weaker as an STS inhibitor compared to parent bis-sulfamate 3. The potential of 4 as an orally dosed anti-tumor agent is confirmed using breast and prostate cancer xenografts. In the MDA-MB-231 model, dramatic reduction in tumor growth or regression was observed, with effects sustained after cessation of treatment. 3-O-Sulfamoylated 2-alkylestradiol-17-O-carbamates and sulfamates have considerable potential as anticancer agents.

Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model

“…This reaction sequence is reported to give the final azide with complete inversion of configuration [30], consistent with its 1 H-NMR data. Finally, because of improved oral bioavailability reported for several steroidal compounds with sulfamate substitutions at C3 [31, 32], we consider it a worthy endeavor to synthesized and test the 3β-sulfamate analog of compound 5 . Thus, 5 was sulfamoylated to afford 3β-O-sulfamoyl-17-(1 H -benzimidazole)androsta-5,16-diene ( 9 ) (Scheme 1) using tert -butoxide and sulfamoyl chloride in DMF [32].…”

Optimisation of Tetrahydroisoquinoline‐Based Chimeric Microtubule Disruptors

“…A long-standing interest in the development of microtubule disruptors as anticancer agents led us to explore whether, through combining the key pharmacophore elements of two series of colchicine site binders, we might generate “chimeric” small molecules with similar activity. In a preliminary report [3] we outlined how, by introducing the A,B-ring elements of the pharmacophore from a series of steroidal microtubule disruptors 1 [4–9] (e.g., 2-methoxyestradiol-3,17- O , O -bis-sulfamate, 2-MeOE2bis-MATE, STX140, 1a ) into a tetrahydroisoquinoline (THIQ) motif and connecting this to a trimethoxyaryl motif commonly found in a range of colchicine site binding natural products (e.g., colchicine 2 ), we could generate novel “chimeric” microtubule disruptors 3,4 (Figure 1). …”

Synthesis, Anti‐tubulin and Antiproliferative SAR of Steroidomimetic Dihydroisoquinolinones

“…[1–6] These compounds exhibit antiproliferative activity against a range of human cancer cell lines and are also capable of inhibiting angiogenesis. This dual mechanism of action can be ascribed to their ability to inhibit normal microtubule dynamics and, in addition to good oral bioavailability and excellent in vivo activity, they proved capable of inhibiting the growth of cell lines resistant to existing microtubule disruptors such as the taxanes.…”