title: Induction of targeted osteogenesis with 3-aryl-2H-benzopyrans and 3-aryl-3H-benzopyrans: Novel osteogenic agents.
abstract: Development of target oriented chemotherapeutics for treatment of chronic diseases have been considered as an important approach in drug development. Following this approach, in our efforts for exploration of new osteogenic leads, substituted 3-aryl-2H-benzopyran and 3-aryl-3H-benzopyran derivatives (19, 20a-e, 21, 22a-e, 26, 27, 28a-e, 29, 31a-b, 32 and 33) have been characterized as estrogen receptor-β selective osteogenic (bone forming) agents. The synthesized compounds were evaluated for osteogenic activity using mouse calvarial osteoblast cells. Four compounds viz20b, 22a, 27and 32 showed significant osteogenic activity at EC50 values 1.35, 34.5, 407 and 29.5pM respectively. Out of these, 20b and 32 were analyzed for their bone mineralization efficacy and osteogenic gene expression by qPCR. The results showed that 20b and 32 significantly increased mineral nodule formation and the transcript levels of BMP-2, RUNX-2 and osteocalcin at 100pM concentrations respectively. Further mechanistic studies of 20b and 32 using transiently knocked down expression of ER-α and β in mouse osteoblast (MOBs) showed that 20b and 32 exerts osteogenic efficacy via activation of estrogen receptor-β preferentially. Additionally, compounds showed significant anticancer activity in a panel of cancer cell lines within the range of (IC50) 6.54-27.79μM. The most active molecule, 22b inhibited proliferation of cells by inducing apoptosis and arresting cell cycle at sub-G0 phase with concomitant decrease in cells at S phase.
authors.affiliation: Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India. Electronic address: atisky2001@yahoo.co.in.
authors.forename: Atul
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India.
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow 226031, India.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Kureel
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow 226031, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hasanain
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow 226031, India.
authors.forename: Praveen
authors.initials: P
authors.lastname: Pandey
authors.affiliation: Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and aromatic Plants, P.O. CIMAP, Kukrail Road, Lucknow 226015, India.
authors.forename: Sarita
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow 226031, India.
authors.forename: Aijaz A
authors.initials: AA
authors.lastname: John
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow 226031, India.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Sarkar
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow 226031, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D034741:RNA, Small Interfering; D000469:Alkaline Phosphatase
keywords: Anticancer; Antiestrogen; Antiosteoporotic; Estrogen; Isoflavone; SERMs