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IJCB 42B(1) 166-172.Pdf Indian Journal of Chemistry Vol. 42B, January 2003, pp. 166-172 Synthesis and biological activity of 16-arylidene derivatives of estrone and estrone methyl ether Maninder Minu* & Dharam Paul lindal University In 5titutc of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India and G Leclercq & M Borras institut Jules Bordet, Association Hospitaliere de Bruxelles. Centre des Tumeurs de I'ULB, Rue Heger-Bordet 1- 1000, Belgiulll Received 24 April 200 I .. accepted (revised) 20 March 2002 The synthesis of 16-arylidene derivatives 3, 4, S, 6, 7. 8. 9, 10, 11, 12, 13, 14 and IS is described. These compounds have been tested at NCI, Bethesda, for their antineoplastic acti vity against the cell panel consisting of 60-ce!l lines and th e compounds 3, 4, S, 6 and 7 have also been tested for their ill vitro estrogenic / antiestrogenic activity; induction of ERE­ dependent luciferase inductio n was measured (MvLN celis). The formation of active steroids by aromatase has It was conceived that selective inhibitors of aroma­ been considered to play an important role in the de­ tase might be useful as a pharmacological tool to de­ velopment of human breast carcinoma t, at least one­ vice successful treatment approach for the hormonal third of all breast cancers establishing that. the estro­ dependent breast cancer. Our efforts were focused on gen-dependent carcinoma regresses following estro­ designing estrogen and estrogen methyl ether deriva­ 2 gen deprivation . In the postmenopausal women, the tives that might inhibit or possess antiestrogenic activ­ production of estrogen takes place in peripheral tissue ity. From these efforts, several 16-arylidine deriva­ 3 from inactive precursors by the action of aromatase . tives of estrone and estrone methyl ether have [t has been documented by several IJboratories that emerged which are reported in this paper. the increased aromatase activity in breast cancer tis­ It was planned to synthesise a series of 16- sue is more as compared to the non-malignant paren­ substituted estrone derivatives (Scheme I). Estrone 3 chyma .4 . The enzyme is the rational target for devd­ was subjected to base-catalysed al dol condensation opment of drugs to treat hormonal-dependent breast with 3,4,5-trimethoxybenzaldehyde; 4-cyanobenzalde­ 5 9 cancer - . hyde; 4-nitrobenzaldehyde, 4-isopropylbenzalde­ Aminoglutethimide 1 is the pioneer drug of non­ hyde and 4-pyridinecarboxaldehyde to get 3 [IR: steroidal competitive aromatase inhibitors, but it lacks 1720 cm' l; IH NMR: () 3.91 (9H: 3,4,5-0CH3) and specificit/. In recent years, clinical research of aro­ 7.40 (lH, vinyl-H)]; 4 [UV: Amax 296.0 11m; IR: C =N matase inhibitors has accelerated exponentially IO,14. stretching at 2240 cm' l; IH NMR showed singlet for Several oral aromatase inhibitors have been demon­ vinyl-H at 8 7.66]; 5 [IR: 1710 cm' l; IH NMR singlet strated to be highly potent and specific inhibitors of for vinyl-H at 8 7.48]; 6 CH NMR showed a doublet estrogen at 8 1.28] and 7 rIR: 1720 cm' l and the IH NMR o showed singlet at 8 7.34 for the vinyl-H]. 'I '\ N I /" - A series of compounds bearing aryl idine moieties (CrC~ at C-16 position in estrone methyl ether was synthe­ ( 1) (2) sized. The compounds 8- 11 were obtained by aldol condensation using potassium hydroxide as catalyst. synth eSlS . IS' , I 8 . V'anous Jl1. d anone d"envatlves h ave a I so For this, estrone methyl ether was condensed with showed good inhibitory effects and more selectivity. 3,4,5-trimethoxybenzaldehyde; 3,4-dimethoxybenza!de­ The 2-(4-pyridylmethylene)-I-indanone 2 showed hyde; cuminaldehyde and vanillin to obtain 8-11 , re­ good inhibitory effectsl9. spectively. MINU el al.: SYNTHESIS OF ESTRONE DERIV ATIVES 167 The structures of these compounds, 8 ['H NMR singlets at 8 3.90 (9H, 3,4,5-0CH3) and 7.38 (vinyl­ H)]; 9 [UV: Amax 334.1 nm; IR: 1720 cm·' and 'H NMR sin glets at 8 3.95 (6H, 3,4-0CH3) and 7.41 (vi nyl-If); 10 [UV: Amax at 308.8 nm; 'H NMR signals RO at 8 1.28 [d, 6H, J=9Hz, -CH(CH3h] and 7.45 (lH, s, o eH vinyl-H) and 11 ['H NMR showed singlets at 8 3.93 5.97 di sappeared Oli exchange) (3) R =H R1 = '/_ '\ OCH3 (-OCH3), (-OH; 0 20 -et ' and 7.40 (vinyl-H)] were determined with the help of OCH3 spectral and elemental analyses. Next, condensation of the aldehydes containing ni ­ R1 = (4) R =H -{}C:N trogen was planned. For thi s, estrone methyl ether was condensed with N,N-dimethylaminobenzalde­ hyde; 4-cyanobenzaldehyde; 4-nitrobenzaldehyde and (5) R=H R1 = -{}N02 4-pyridinecarboxaldehyde to get 12-15, respectively. The spectral analyses of these compounds, 12 [UV: CH Amax at 382.4 nm, IR: 1730 cm-'; 'H NMR: singlets at -{} / 3 (6) R=H R1 = CH 8 3.06 {6H, -N (C H3)2 } and 7.41 (lH, - .......... 3 CH vinyl-H)]; 13 [UV: Amax at 294.0 nm ; IR showed C == N stretching at 2230 cm·'; and proton resonance (7) R =H R1 = 1 ~N singlet for vinyl-H at 8 7.43]; 14 [UV: Amax at 278.2 nm; IR: 1730 cm-'; 'H NMR singlet at 8 7.48 (v in yl­ OC H H) and 15 [UV: Amax at 278.6 nm; IR: 1720 cm·' and NMR singlet at 8 7.36 for the vinyl-H] , and CHN R1 = (8) R= CH3 -et'/_ '\ OCH3' analyses confirmed the structures. OCH3 The configuration in both estrone methyl ether as well as in estrone series is believed to be Z on the ba­ OOH sis of 'H NMR spectroscopy as described earlier20. , (9) R= CH 3 R1 = -6'/_ '\ OCH3 Biological activities Antineoplastic activity CH -{} / 3 (10) R =CH3 R1 = CH The compounds 3 (DPJ-717), 4 (OPJ-716), 5 (OPJ- - .......... CH 3 718), 7 (OPJ-734), 11 OPJ-715), 12 (OPJ-708), 13 (OPJ-720) and 15 (OPJ-714) have been tested fm· oeH antineoplastic activity at National Cancer In stitute, , Bethesda, Maryland, USA, in vitro again st the cell (11) R= CH 3 R1 = -6'/_ '\ Oft panel consisting of 60 lines at a minimum of five con­ centrations at IO-fold di lutions. A 48 hr continuous CH3 drug exposure protocol was used, and a sul forhoda­ (12) R= CH3 R1 = -{}N/ - .......... CH 3 minc B (SRB) protein assay was used to estimate ceil viability or growth. The results obtained indicated th at the compounds have statistically in significant anti ­ (13) R1 = R= CH3 -{}C:N neoplastic activity for further studies. Estrogenic/ Antiestrogenic activity (14) R= CH3 R1 = N0 -{} 2 Compounds 3 (DPJ-717), 4 (DPJ-716), 5 (DPJ- 718), 6 (DPJ-721 ) and 7 DPJ-734) were tested for their in vitro estrogenic / antiestrogeni c activity: in­ (15) R= CH 3 R1 = -eN:==J duction cf ERE-dependent luciferase induction was Scheme I measured (MVLN cells), all compounds induced the 168 INDIAN J. CHEM., SEC B, JA NUARY 2003 I expression of this reporter gene with an efficiency at tra in KBr (umax in cm- ) on Perkjn-Elmer 882, UV least I,OOO-foid less than EI (optimal induction spectra in methanol (A.max in nm figures within paren­ 9 - 10. ); DPl-721 was the less effective compound. thesis refer to log £ values), on a Lambda 15 spectro­ Hence, all compounds shared weak estrogenic activ­ photometer models respectively and mass spectra on ity. Binding affinity for ER was also assessed with a V6-11-250 1 70S. The purity of the compounds was human recombinant produced in yeast (Table I). establi shed by TLC, which was prepared with silica Values were weak ( I % of EI at maximum), in agree­ gel G according to Stahl (E. Merck) usin g ethyl ace­ ment with luciferase data (Figures1 and 2). tate. [odine was used to develop the TLC plates. Ele­ mental analyses were calTied out on a Perkin-Elmer Experimental Section 2400 CHN elemental analyzer. Anhydrous sodium Melting points reported are uncorrected. IH NMR sulphate was used as a drying agent. spectra were recorded on AC-300F, 300 MHz, Varian 16-(3, 4, 5-TrimethoxybenzyJidene)-17 -oxo-1 , 3, EM-390, 60 MHz spectrometers using TMS as an 5 (1 0)-estratrien- 3~-ol 3. A solution of estrone (0.25 internal standard (chemical shifts in 8, ppm), IR spec- g), potassium hydroxide (0.25 g) and 3, 4, 5- trimethoxybenzaldehyde (0.3 g) in methanol (SO mL ) Table I - Measurement of binding affinity for ER was refluxed for 15 hr. The completion of reaction Compd Code Binding affinit y for was monitored by TLC and the solution was concen­ hER (RBA) trated in vacuo. Ice-cold water was added, the suspen­ EI = 100 sion was acidified with conc. HCI and the precipitate was removed by fi ltration, dried and crystallised from 4 DPJ - 716 0.1 dichloromethane-methanol to afford 3 (0.2 g, 3 DPJ - 717 1.0 48.78%), m.p. 144-52°; UV: 319.6 (4.22); IR: 3420 5 DPJ - 718 0.1 (O-H), 1720 (C=O) 1260; IH NMR: 1.00 (3H, s, 18- 6 DPJ - 721 < 0.1 CHJ), 3.91 (9H, s, 3, 4, 5-0CH3), 5.13 (lH, s, 3-0H; 7 DPJ - 734 1.0 disappeared on 0 20 exchange) 6.6 1 (I H, d, J=3Hz, 4- 717, 734 > 716, 718 > 72 I CH of estrone), 6.67 ( I H, dd, J=3Hz and 9Hz, 2-CH of estrone), 6.80 (2H, s, 2-CH and 6-CH of 16-(3,4,5- trimethoxybenzylidene)), 7.18 (lH.
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