Atul Goel

Methoxylated isoflavones, cajanin and isoformononetin, have non‐estrogenic bone forming effect via differential mitogen activated protein kinase (MAPK) signaling

Following a lead obtained from stem‐bark extract of Butea monosperma, two structurally related methoxyisoflavones; cajanin and isoformononetin were studied for their effects in osteoblasts. Cajanin had strong mitogenic as well as differentiation‐promoting effects on osteoblasts that involved subsequent activation of MEK‐Erk and Akt pathways. On the other hand, isoformononetin exhibited potent anti‐apoptotic effect in addition to promoting osteoblast differentiation that involved parallel activation of MEK‐Erk and Akt pathways. Unlike genistein or daidzein, none of these two compounds appear to act via estrogen receptors in osteoblast. Once daily oral (by gavage) treatment for 30 consecutive days was given to recently weaned female Sprague–Dawley rats with each of these compounds at 10.0 mg kg−1 day−1 dose. Cajanin increased bone mineral density (BMD) at all skeletal sites studied, bone biomechanical strength, mineral apposition rate (MAR) and bone formation rate (BFR), compared with control. BMD levels at various anatomic positions were also increased with isoformononetin compared with control however, its effect was less potent than cajanin. Isoformononetin had no effect on the parameters of bone biomechanical strength although it enhanced MAR and BFR compared with control. Isoformononetin had very mild uterotrophic effect, whereas cajanin was devoid of any such effect. Our data suggest that cajanin is more potent than isoformononetin in accelerating peak bone mass achievement. To the best of our knowledge, this work represents the first attempt to elucidate structure‐activity relationship between the two methoxylated isoflavones regarding their effects in osteoblasts and bone formation. J. Cell. Biochem. 108: 388–399, 2009.

Vapor-Phase Processable Novel Nonplanar Donor−Acceptor Quateraryls for Blue OLEDs#

A novel series of thermally stable blue light emitting quateraryls with a piperidine donor and a nitrile acceptor was prepared from a ketene- S, S-acetal under mild conditions without using an organometal catalyst. The performance of a blue quateraryl 6e was investigated by fabricating a multilayer OLED with a configuration of ITO/PEDOT:PSS (40 nm)/quateraryl (60 nm)/BCP (6 nm)/Alq(3) (20 nm)/LiF (0.5 nm)/Al (200 nm), which exhibited blue emission with a low turn on voltage of 4 V at a brightness of 0.22 cd/m(2).

Medicarpin inhibits osteoclastogenesis and has nonestrogenic bone conserving effect in ovariectomized mice

Medicarpin, a pterocarpan class of naturally occurring benzopyran furanobenzene compound was synthesized in gram scale to investigate its effects on murine bone cells and in ovariectomized (OVx) mice. Medicarpin, at as low as 10(-10)M suppressed osteoclastogenesis in bone marrow cells (BMCs). Medicarpin-induced apoptosis of mature osteoclasts isolated from long bones. Effects of medicarpin in osteoclasts appear to be independent of estrogen receptor (ER) activation as ICI 180,782 failed to abrogate its effects on osteoclasts. In calvarial osteoblasts, medicarpin (10(-10)M) blocked nuclear factor kappaB (NF-kappaB) signaling assessed by tumor necrosis factor alpha (TNFalpha)-stimulated nuclear translocation of p65 subunit of NF-kappaB. Medicarpin also inhibited the expression of TNFalpha in mouse calvarial osteoblasts. This effect was ER dependent as ICI 180,782 reversed the suppressive effect of medicarpin on TNFalpha mRNA levels in osteoblasts. In addition, like 17beta-estradiol, presence of medicarpin inhibited TNFalpha-induced upregulation of interleukin-1, and -6 mRNA levels in osteoblasts. In co-cultures consisting of calvarial osteoblasts and BMCs, presence of medicarpin increased osteoprotegerin (OPG)/receptor activator of NF-kappaB ligand (RANKL) ratio and reduced mRNA levels of osteoclast markers including tartrate-resistant acid phosphatase and RANK. OVx mice administered medicarpin (10.0mgkg(-1)day(-1)) orally for 30days had reduced formation of osteoclasts but increased formation of osteoprogenitor cells in BMCs compared with OVx+vehicle group. Medicarpin treatment to OVx mice maintained parameters of trabecular microarchitecure. Medicarpin exhibited no uterine estrogenicity. Our findings point towards direct and indirect inhibitory effects of medicarpin on osteoclastogenesis in vitro that contribute to its bone sparing effect in OVx mice.

Total extract and standardized fraction from the stem bark of Butea monosperma have osteoprotective action: evidence for the nonestrogenic osteogenic effect of the standardized fraction.

Objective: The aim of this study was to determine the skeletal effects of Butea total extract (BTE) and its acetone soluble fraction (ASF) from Butea monosperma, which is rich in methoxyisoflavones, in ovariectomized (OVx) rats, a model for postmenopausal bone loss. Methods: BTE (1.0 g kg−1 d−1) and ASF (100 mg kg−1 d−1) were given orally for 12 weeks to adult OVx rats. The sham-operated and ovariectomy + vehicle groups served as controls. Bone mineral density, osteoid formation (mineral apposition rate and bone formation rate), bone microarchitecture, and bone turnover/resorption markers were studied. Phytoestrogens in rats given BTE and ASF were analyzed by high-performance liquid chromatography. One-way analysis of variance was used to test significance of effects. Results: OVx rats treated with either BTE or ASF exhibited increased bone mineral density in trabecular bones and improved trabecular microarchitecture compared with the ovariectomy + vehicle group. ASF treatment was more efficient than BTE treatment in maintaining trabecular microarchitecture. Serum osteocalcin and urinary type 1 collagen levels in OVx rats treated with either BTE or ASF were significantly lower than those of the ovariectomy + vehicle group. ASF treatment led to increased mineral apposition rate and bone formation rate compared with ovariectomy + vehicle, whereas BTE had no such effect. In the uterotropic assay, BTE was mildly estrogenic in adult OVx rats. In immature rats, BTE exhibited both estrogenicity and antiestrogenicity. ASF had neither uterine estrogenicity nor antiestrogenicity. Analysis of phytoestrogens revealed significant enrichment of cladrin, isoformononetin, and medicarpin in ASF over BTE. Conclusions: Derived from B monosperma, ASF at a 10-fold lower dose than that of BTE was effective in preventing OVx-induced bone loss and stimulated new-bone formation.

Medicarpin, a legume phytoalexin, stimulates osteoblast differentiation and promotes peak bone mass achievement in rats: evidence for estrogen receptor β-mediated osteogenic action of medicarpin.

Dietary isoflavones including genistein and daidzein have been shown to have favorable bone conserving effects during estrogen deficiency in experimental animals and humans. We have evaluated osteogenic effect of medicarpin (Med); a phytoalexin that is structurally related to isoflavones and is found in dietary legumes. Med stimulated osteoblast differentiation and mineralization at as low as 10⁻¹⁰ M. Studies with signal transduction inhibitors demonstrated involvement of a p38 mitogen activated protein kinase-ER-bone morphogenic protein-2 pathway in mediating Med action in osteoblasts. Co-activator interaction studies demonstrated that Med acted as an estrogen receptor (ER) agonist; however, in contrast to 17β-estradiol, Med had no uterine estrogenicity and blocked proliferation of MCF-7 cells. Med increased protein levels of ERβ in osteoblasts. Selective knockdown of ERα and ERβ in osteoblasts established that osteogenic action of Med is ERβ-dependent. Female Sprague-Dawley (weaning) rats were administered Med at 1.0- and 10.0 mg.kg⁻¹ doses by gavage for 30 days along with vehicle control. Med treatment resulted in increased formation of osteoporgenitor cells in the bone marrow and osteoid formation (mineralization surface, mineral apposition/bone formation rates) compared with vehicle group. In addition, Med increased cortical thickness and bone biomechanical strength. In pharmacokinetic studies, Med exhibited oral bioavailability of 22.34% and did not produce equol. Together, our results demonstrate Med stimulates osteoblast differentiation likely via ERβ, promotes achievement of peak bone mass, and is devoid of uterine estrogenicity. In addition, given its excellent oral bioavailability, Med can be potential osteogenic agent.

A Convenient Synthesis and Hepatoprotective Activity of Imidazo(1,2-c)pyrimido(5,4-e)pyrimidine, Tetraazaacenaphthene and Tetraazaphenalene from Cyclic Ketene Aminals Through Tandem Addition-Cyclization Reactions {

A novel one-pot synthesis of imidazo[1,2-c]pyrimido[5,4-e]pyrimidinones (2), tetraazaacenaphthene-3,6-diones (4), tetarazaphenalene-1,7-dione (4d) is delineated from the reaction of cyclic ketene aminal (1) and alkyl or aryl isothiocyanate through tandem addition-cyclization reactions. However, reaction of ketene aminal (1a) with alkyl isothiocyanate only yielded angularly cyclized product 5 which did not react further to yield 6. The structure of 2c and 4d was ascertained by single crystal X-ray diffraction analysis which demonstrated a network of various inter- and intramolecular interactions, responsible for the stability and packing of the molecules in the crystalline state. Some of the compounds (2a--h) were screened for hepatoprotective activity but only 2a was found most effective.

Synthesis of thiophenes and thieno[3,2-c]pyran-4-ones as antileishmanial and antifungal agents

Abstract A series of highly functionalized thiophene ( 2 ) and thieno[3,2-c]pyran-4-one( 4 ) derivatives have been synthesized and evaluated for their antileishmanial and antifungal activities.

Synthesis, electrochemical and optical properties of stable yellow fluorescent fluoranthenes.

A novel series of thermally stable yellow light emitting fluoranthenes with an amine donor and a nitrile acceptor was prepared from a ketene-S,S-acetal under mild conditions without using an organometal catalyst. The organic light emitting device of yellow fluoranthene 10b exhibited substantially low turn-on voltage (2.6 V) and maximum brightness of 470 Cd/m(2) with luminance efficiency of 2.0 Cd/A without using any dopant.

Synthesis of bridgedhead azolo[3,2-a]pyrimidines and imidazo[2,1-b]thiazines through ring transformation of 2H-pyran-2-ones

Suitably functionalized 3-carbomethoxy/cyano-2H-pyran-2-ones are excellent synthons for the synthesis of arenes and heteroarenes of therapeutic importance. The compounds 6-aryl-3-cyano-4-methylsulfanyl-2H-pyran-2-ones have been transformed into bridgedhead azolopyrimidines and imidazothiazines through thermal and base-induced ring transformation reactions with aminoazoles and imidazolidin-2-thiones, respectively.

New Fluoranthene FLUN-550 as a Fluorescent Probe for Selective Staining and Quantification of Intracellular Lipid Droplets

A new class of live cell permeant, nontoxic fluoranthene-based fluorescent probe (FLUN-550) having a high Stokes shift in aqueous medium has been discovered. It showed selective staining of lipid droplets (LDs, dynamic cytoplasmic organelles) at a low concentration without background noise in in vitro live cell imaging of 3T3-L1 preadipocytes, J774 macrophages, MCF7 breast cancer cells, and single-celled, parasitic protozoa Leishmania donovani promastigotes and in vivo nonparasitic soil nematode C. elegans.