Differentiation of skeletal osteogenic progenitor cells to osteoblasts with 3,4-diarylbenzopyran based amide derivatives: Novel osteogenic agents

Atul Gupta; Imran Ahmad; Jyoti Kureel; Aijaz A John; Eram Sultan; Debabrata Chanda; Naresh Kumar Agarwal; Alauddin; Wahajuddin; S Prabhaker; Amita Verma; Divya Singh

doi:10.1016/j.ejmech.2016.05.023

Differentiation of skeletal osteogenic progenitor cells to osteoblasts with 3,4-diarylbenzopyran based amide derivatives: Novel osteogenic agents

Eur J Med Chem. 2016 Oct 4:121:82-99. doi: 10.1016/j.ejmech.2016.05.023. Epub 2016 May 9.

Authors

Atul Gupta¹, Imran Ahmad², Jyoti Kureel³, Aijaz A John³, Eram Sultan⁴, Debabrata Chanda⁴, Naresh Kumar Agarwal⁵, Alauddin⁵, Wahajuddin⁶, S Prabhaker⁷, Amita Verma², Divya Singh³

Affiliations

¹ Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, PO. CIMAP, Kukrail Road, Lucknow, 226015, India. Electronic address: atisky2001@yahoo.co.in.
² Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, PO. CIMAP, Kukrail Road, Lucknow, 226015, India.
³ Division of Endocrinology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226031, India.
⁴ Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, PO. CIMAP, Kukrail Road, Lucknow, 226015, India.
⁵ Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226031, India; Department of Zoology, HNB Garhwal Central University, Badshahi Thaul Campus, Tehri Garhwal 249 199, Uttarakhand, India.
⁶ Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226031, India.
⁷ National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India.

PMID: 27236065
DOI: 10.1016/j.ejmech.2016.05.023

Abstract

A series of 3,4-diarylbenzopyran based amide derivatives was synthesized and evaluated for osteogenic activity in in vitro and in vivo models of osteoporosis. Compounds 17a, 21b-c and 22a-b showed significant osteogenic activity in osteoblast differentiation assay. Among the synthesized compounds, 22b was identified as lead molecule which showed significant osteogenic activity at 1 pM concentration in osteoblast differentiation assay and at 1 mg kg(-1) body weight dose in estrogen deficient balb/c mice model. In vitro bone mineralization and expression of osteogenic marker genes viz BMP-2, RUNX-2, OCN, and collagen type 1 further confirmed the osteogenic potential of 22b. Gene expression study for estrogen receptor α and β (ER-α and ER-β) in mouse calvarial osteoblasts (MCOs) unveiled that possibly 22b exerted osteogenic efficacy via activation of Estrogen receptor-β preferentially. In vivo pharmacokinetic, estrogenicity and acute toxicity studies of 22b showed that it had good bioavailability and was devoid of uterine estrogenicity at 1 mg kg(-1) and inherent toxicity up to 1000 mg kg(-1) body weight dose respectively.

Keywords: Antiosteoporotic; Benzopyran; Estrogen; Isoflavone; Osteogenic.

MeSH terms

Amides / chemistry*
Amides / pharmacokinetics
Amides / pharmacology
Animals
Benzopyrans / chemistry
Benzopyrans / pharmacokinetics
Benzopyrans / pharmacology*
Biological Availability
Cell Differentiation / drug effects*
Estrogen Receptor beta / metabolism
Mice
Mice, Inbred BALB C
Osteoblasts / cytology*
Osteogenesis / drug effects
Osteoporosis / chemically induced
Stem Cells / cytology*
Structure-Activity Relationship

Substances

Amides
Benzopyrans
Estrogen Receptor beta