Abstract
(Mercaptophenyl)naphthylmethane derivatives were synthesized as novel estrogen receptor binding ligands. [4-(Methylsulfonyl)phenyl](naphth-1-yl)ketone shows a very promising activity towards osteoporosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1269-1277 |
| Number of pages | 9 |
| Journal | Monatshefte fur Chemie |
| Volume | 139 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2008 |
| Externally published | Yes |
Bibliographical note
Funding Information:with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to give the desired compound as oil. (4-Ethylthiophenyl)(naphth-1-yl)ketone (33, C19H16OS) Yield 67.8%; IR (Neat): ¼ 1677 (C¼O), 1595, 1415 (ArH), 773, 665 (C–S) cm1; 1H NMR (CDCl3): ¼ 1.25 (t, 3H, CH2CH3), 3.3 (q, 2H, CH2CH3), 7.25–9.10 (m, 11H, ArH) ppm; MS: m=z¼ 292. (4-Isopropylthiophenyl)(naphth-1-yl)ketone (34, C20H18OS) Yield 60.4%; IR (Neat): ¼ 1668 (C¼O), 1582, 1441, (ArH), 668, 759 (C–S) cm1; 1H NMR (CDCl3): ¼ 1.25 (d, 6H, CH(CH3)2), 3.5 (m, 1H, CH(CH3)2), 7.26–9.10 (m, 11H, ArH) ppm; MS: m=z¼ 306. (4-Piperidinylethylthiophenyl)(naphth-1-yl)ketone (35, C24H25NOS) A mixture of 212 mg (4-mercaptophenyl)(naphth-1-yl)ketone (0.76 mmol), 253 mg 1-(2-chloroethyl)piperidine hydrochloride (1.38 mmol), and 553 mg anhydrous potassium carbonate (4.0 mmol) in 15 cm3 dry acetone was refluxed for 15–18 h. Potassium carbonate was filtered off and acetone was distilled off. The reaction mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated to give an oil. This was passed through a basic alumina column using n-hexane–benzene as eluent to yield the desired product as oil. Yield 44.2%; IR (Neat): ¼ 3429 (amine), 1704 (C¼O), 1610, 1509 (ArH), 757, 661 (C–S) cm1; 1H NMR (CDCl3): ¼ 1.18–1.32 (m, 6H, 3CH2 of piperidine), 2.17 (m, 4H, 2NCH2), 4.28–4.33 (t, 2H, CH2N), 4.53–4.59 (t, 2H, SCH2), 7.27–8.94 (m, 11H, ArH) ppm; MS: m=z¼ 375. Animals and chemicals Fertilized chicken eggs purchased from Government Poultry Farm, Lucknow on the day of ovulation (day 1) were incubated at 37C in humidified air. Each egg was observed for embryonic growth on egg kindler and manually rotated at least once every 24 h. BGJb bone culture medium, parathyroid hormone (PTH, aa 1–34, and molecular weight 4117.7), bovine serum albumin (fraction V), HEPES, streptomycin, penicillin, DMSO, PPO, POPOP, and methoxyethanol were purchased from Sigma Chemical Company, USA. Toluene was purchased from Qualigen Fine Chemicals, Mumbai, 45CaCl2 (specific activity: 0.185–1.85 g Bq=mg Ca) from Amersham Pharmacia Biotech, England and kits for biochemical markers of bone turnover from Boehringer Mannheim, Germany. All other chemicals were of analytical grade. Experimental design Antiresorptive activity in vitro The antiresorbing activity of test agents was assessed as detailed earlier [18]. Briefly, femur bones isolated from chick embryos on day 11 post-ovulation were cleared of adhering connective tissue by carefully rotating each bone on dry Whatman (I) filter paper under a stereomicroscope. Each femur was placed in a drop of phosphate buffered saline (PBS) before culturing in 300 mm3 of BGJb medium (pH 7.3) supplemented with penicillin (0.075 mg=mm), streptomycin (0.05 mg=mm), HEPES (2.382 mg=mm), and bovine serum albumin (1 mg=mm) in sterile 48-=96-well plates at 37C under an atmosphere of 5% CO2 in air for 24 h. Bones were transferred to BGJb culture medium containing 45CaCl2 (0.5Ci= 300 mm3 medium) and incubated for 3 h at 37C under 5% CO2 in air. Bones were then washed three times with BGJb medium for 3 h at 37C under 5% CO2 in air. Labeled bones were transferred to BGJb medium containing PTH (0.4M) and chase cultured for 96 h in presence or absence of test agents or vehicle (ethanol=DMSO; final concentration 0.1%) in 300 mm3 of BGJb medium. Contralateral femur of each fetus served as corresponding control. Culture medium with respective treatment in each well was changed after 48 h. On termination of culture, bones were transferred to 0.1N HCl for 24 h. Radioactivity due to 45Ca in spent medium collected at 48 and 96 h of culture and HCl extract was quantified by Liquid Scintillation Spectrophotometer (LKB Wallac 1282 Gamma Counter, Finland) in 10 cm3 of scintillation fluid (PPO: 2.00 g, POPOP: 0.05 g, toluene: 500 cm3, methoxyethanol: 500 cm3). One set of bones was heat killed by keeping in PBS in sterile tubes in boiling water for 15 min and cultured in parallel to assess viability of bones in culture system. Bone resorbing activity was expressed as percentage of 45Ca released into culture medium and the effect of test agents as percent of corresponding contralateral control or T=C (Treatment=Control) ratio as shown below. T=C ratio close to unity shows lack of antiresorbing activity of the test agent. 45Ca resorptionð%Þ ¼ 45Ca released into the medium ð45Ca released into the medium þ 45Ca remaining inthe bone ðHCl extractÞÞ 100 T=C ratio ¼ 45Ca resorption in presence of PTHþ test agent 45Ca resorption in presence of PTHþ vehicle Acknowledgements The authors thank the Ministry of Health and Family Welfare, Government of India for financial support. One of us (MMS) thanks the Indian Council of Medical Research, New Delhi for appointment as Emeritus Medical Scientist. References 1. Rosen CJ (2005) N Engl J Med 353:595 2. Ray S, Sangita (2004) Drugs of the Future 29:185 3. Reese J, Zhao X, Ma W-G, Brown N, Maziasz TJ (2001) Endocrinol 142:3198 4. Rankin JC, Ledford BE, Baggett B (1979) Biol Reprod 20:399 5. Mehrotra PK (1982) Ind J Exp Boil 20:719 6. Verma P, Arora PK, Salman M, Ray S, Srimal RC (1989) Indian J Pharm Sci 51:48 1276 Sangita et al.
Keywords
- (Mercaptophenyl)naphthylmethane
- Osteoporosis
- Sulfide
- Sulfones
- Thiophenol