Light Induced Proton Coupled Charge Transfer Triggers Counterion Directional Translocation.

We demonstrate directed translocation of ClO4 - anions from cationic to neutral binding site along the synthetized BPym-OH dye molecule that exhibits coupled excited-state intramolecular proton-transfer (ESIPT) and charge-transfer (CT) reaction (PCCT). The results of steady-state and time-resolved spectroscopy together with computer simulation and modeling show that in low polar toluene the excited-state redistribution of electronic charge enhanced by ESIPT generates the driving force, which is much stronger than by CT reaction itself and provides more informative gigantic shifts of fluorescence spectra signaling on ultrafast ion motion. The associated with ion translocation red-shifted fluorescence band (at 750 nm, extending to near-IR region) appears at the time ~83 ps as a result of electrochromic modulation of PCCT reaction. It occurs at substantial delay to PCCT that displayed fluorescence band at 640 nm and risetime of <200 fs. Thus, it becomes possible to visualize the manifestations of light-triggered ion translocation and of its driving force by fluorescence techniques and to separate them in time and energy domains.

From Terminal to Spiro-Phosphonium Acceptors, Remarkable Moieties to Develop Polyaromatic NIR Dyes.

Phosphonium-based compounds gain attention as promising photofunctional materials. As a contribution to the emerging field, we present a series of donor-acceptor ionic dyes, which were constructed by tailoring phosphonium (A) and extended π-NR2 (D) fragments to an anthracene framework. The alteration of the π-spacer of electron-donating substituents in species with terminal -+ PPh2 Me groups exhibits a long absorption wavelength up to λabs =527 nm in dichloromethane and shifted the emission to the near-infrared (NIR) region (λ=805 nm for thienyl aniline donor), although at low quantum yield (Φ<0.01). In turn, the introduction of a P-heterocyclic acceptor substantially narrowed the optical bandgap and improved the efficiency of fluorescence. In particular, the phospha-spiro moiety allowed to attain NIR emission (797 nm in dichloromethane) with fluorescence efficiency as high as Φ=0.12. The electron-accepting property of the phospha-spiro constituent outperformed that of the monocyclic and terminal phosphonium counterparts, illustrating a promising direction in the design of novel charge-transfer chromophores.

Chronic superphysiologic AMH promotes premature luteinization of antral follicles in human ovarian xenografts.

Anti-Müllerian hormone (AMH) is produced by growing ovarian follicles and provides a diagnostic measure of reproductive reserve in women; however, the impact of AMH on folliculogenesis is poorly understood. We cotransplanted human ovarian cortex with control or AMH-expressing endothelial cells in immunocompromised mice and recovered antral follicles for purification and downstream single-cell RNA sequencing of granulosa and theca/stroma cell fractions. A total of 38 antral follicles were observed (19 control and 19 AMH) at long-term intervals (>10 weeks). In the context of exogenous AMH, follicles exhibited a decreased ratio of primordial to growing follicles and antral follicles of increased diameter. Transcriptomic analysis and immunolabeling revealed a marked increase in factors typically noted at more advanced stages of follicle maturation, with granulosa and theca/stroma cells also displaying molecular hallmarks of luteinization. These results suggest that superphysiologic AMH alone may contribute to ovulatory dysfunction by accelerating maturation and/or luteinization of antral-stage follicles.

Multiple Emission of Phosphonium Fluorophores Harnessed by the Pathways of Photoinduced Counterion Migration.

In the emerging field of intramolecular charge transfer induced counterion migration, we report the new insights into photophysical features of luminescent donor-acceptor phosphonium dyes (D-π-)n A+ [X- ] (π=-(C6 H4 )x -). The unique connectivity of the phosphorus atom affords multipolar molecules with a variable number of arms and the electronic properties of the acceptor group. In the ion-paired form, the transition from dipolar to quadrupolar configuration enhances the low energy migration-induced band by providing the additional pathways for anion motion. The multipolar architecture, adjustable lengths of the π-spacers and the nature of counterions allow for efficient tuning of the emission and achieving nearly pure white light with quantum yields around 30 %. The methyl substituent at the phosphorus atom reduces the rate of ion migration and suppresses the red shifted bands, simultaneously improving total emission intensity. The results unveil the harnessing of the multiple emission of phosphonium fluorophores by anion migration via structure and branching of donor-acceptor arms.

Counterion Migration Driven by Light-Induced Intramolecular Charge Transfer.

A series of D-π-A + pyridinium compounds, in which D = -NPh2 and A+ = -PyMe+ are linked by various amounts of linear phenyl spacers, were strategically designed and synthesized. Their characterization revealed the presence of excited-state intramolecular charge transfer (ESICT) that triggers a corresponding response from the counterion. In medium and strong polar solvents, the fast solvent relaxation occurring after ESICT overwhelms the counterion effect, showing typical emission solvatochromism. In weakly polar solvents, ESICT induces counteranion migration for electrostatic stabilization, the time scale of which is dependent on the radius of the counteranion, the length of the π-linker, and the viscosity of the solvent. In low-viscosity organic solvents such as toluene, counteranion migration occurs within several tens to hundreds of picoseconds, resulting in a time-dependent continuous emission that can be resolved from the spectral temporal evolution. Concrete evidence for this is provided by the chemical synthesis of a D-π-A + pyridinium-sulfur trioxide- zwitterion, where anion migration is restricted due to its internally locked ion pair. As a result, only a single emission band can be observed. These comprehensive studies prove that the ion migration process may be significant for a wide range of ESICT-type ionic fluorophores. Such an ionic movement, triggered by optically pumped ESICT of the D-π-A + dyad, is similar to the molecular machine driven by the redox reaction, but with a facile access and fast response.

Chapter Open for the Excited-State Intramolecular Thiol Proton Transfer in the Room-Temperature Solution.

We report here, for the first time, the experimental observation on the excited-state intramolecular proton transfer (ESIPT) reaction of the thiol proton in room-temperature solution. This phenomenon is demonstrated by a derivative of 3-thiolflavone (3TF), namely, 2-(4-(diethylamino)phenyl)-3-mercapto-4H-chromen-4-one (3NTF), which possesses an -S-H···O═ intramolecular H-bond (denoted by the dashed line) and has an S1 absorption at 383 nm. Upon photoexcitation, 3NTF exhibits a distinctly red emission maximized at 710 nm in cyclohexane with an anomalously large Stokes shift of 12 230 cm-1. Upon methylation on the thiol group, 3MeNTF, lacking the thiol proton, exhibits a normal Stokes-shifted emission at 472 nm. These, in combination with the computational approaches, lead to the conclusion of thiol-type ESIPT unambiguously. Further time-resolved study renders an unresolvable (<180 fs) ESIPT rate for 3NTF, followed by a tautomer emission lifetime of 120 ps. In sharp contrast to 3NTF, both 3TF and 3-mercapto-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one (3FTF) are non-emissive. Detailed computational approaches indicate that all studied thiols undergo thermally favorable ESIPT. However, once forming the proton-transferred tautomer, the lone-pair electrons on the sulfur atom brings non-negligible nπ* contribution to the S1' state (prime indicates the proton-transferred tautomer), for which the relaxation is dominated by the non-radiative deactivation. For 3NTF, the extension of π-electron delocalization by the diethylamino electron-donating group endows the S1' state primarily in the ππ* configuration, exhibiting the prominent tautomer emission. The results open a new chapter in the field of ESIPT, covering the non-canonical sulfur intramolecular H-bond and its associated ESIPT at ambient temperature.

Correlation between Kinetics and Thermodynamics for Excited-State Intramolecular Proton Transfer Reactions.

Finding the relation between thermodynamics and kinetics for a reaction is of fundamental importance. Here, the thermodynamics and kinetics correlation of excited-state intramolecular proton transfer (ESIPT) was investigated by the TD-DFT calculation under the CAM-B3LYP/6-311+G** level. We choose the family 2-(2'-aminophyenyl)benzothiazole and its amino derivatives as paradigms, which all possess the NH-type intramolecular hydrogen bond (H-bond), and investigate the corresponding ESIPT reaction. The H-bond strength can be systematically tuned, so both activation energy ΔG‡ and free energy difference between proton transfer tautomer (T*, product) and normal species (N*, reactant) ΔGT*-N* can be varied. To minimize the environmental interference such as solvent external H-bond and polarity perturbation, a nonpolar solvent such as cyclohexane is chosen as a bath with a polarizable continuum solvation model for the calculation. As a result, the comprehensive computational approach reveals a linear relationship between ΔGT*-N* and ΔG‡, which can be expressed as ΔG‡ = ΔG0 + αΔGT*-N*. The fundamental insight is reminiscent of the Bell-Evans-Polanyi (BEP) principle where α represents the character of the position of the transition state along the proton motion coordinate. In other words, the more exergonic the ESIPT reaction is, the faster the proton transfer rate can be observed. To verify that such a correlation is not a sporadic event, another ESIPT family with an -OH proton, 1-hydroxy-11H-benzo[b]fluoren-11-one and its derivatives, was also investigated and proved to follow the BEP principle as well. Unlike the quantum mechanics description of proton transfer where either proton tunneling is dominant or solute/solvent is coupled in ESIPT, this work demonstrates that reaction kinetics and thermodynamics are strongly correlated within the same class of ESIPT molecules with an intrinsic barrier free from solvent perturbation, being faster with the more exergonic reaction.

Exogenous insulin-like growth factor 1 accelerates growth and maturation of follicles in human cortical xenografts and increases ovarian output in mice.

OBJECTIVE: To measure the influence of exogenous insulin-like growth factor 1 (IGF1) on follicle growth and maturation in human ovarian cortical xenografts. DESIGN: Xenotransplantation model. SETTING: University-based research laboratory. PATIENTS/ANIMALS: Ovarian tissue was donated with consent and institutional review board approval by brain-dead organ donors or patients undergoing ovarian tissue cryopreservation for fertility preservation. Cortical fragments were transplanted into immunocompromised mice. INTERVENTIONS: Cryopreserved ovarian cortical fragments from four women (aged 19, 25, 33, and 46 years) were transplanted into the gluteus muscle of immunocompromised mice in a fibrin matrix containing endothelial cells that were transduced with lentiviral particles encoding secreted IGF1. Xenografts were recovered after 3, 8, and 14 weeks. In addition, C57/Bl6 mice underwent intraovarian injection of saline or recombinant IGF1 (60 µg), followed by superovulation, analysis of ethynyl-deoxyuridine incorporation, and ribonucleic acid sequencing of the whole ovaries. MAIN OUTCOME MEASURES: For xenografts: follicle count and distribution; antral follicle count; and corpora lutea/albicans count. For mice: follicle count and distribution; oocyte yield, ethynyl-deoxyuridine incorporation (granulosa cell proliferation); and ovarian transcriptomic signature. RESULTS: At 3 weeks, xenografts in the IGF1 condition revealed a decreased percentage of primary follicles and increased percentage of secondary follicles that were concentrated in the preantral subtype; at 8 weeks, an increase in secondary follicles was concentrated in the simple subtype; after 14 weeks, primordial follicles were reduced, and while the number of advanced follicles did not power the experiment to demonstrate significance, antral follicles reduced and corpora lutea increased. Supporting experiments in mice revealed an increase in normal oocytes following intraovarian injection of recombinant IGF1 (60 µg) as well as increased proliferative index among follicles of secondary and preantral stages. Ribonucleic acid sequencing analysis of the whole ovaries following injection of recombinant IGF1 (25 µg) revealed an acute (24 hours) upregulation of transcripts related to steroidogenesis and luteinization. CONCLUSIONS: Exogenous IGF1 advances the pace of growth among primordial, primary, and secondary stage follicles but results in near absence of antral stage follicles in long-term (14 weeks) xenografts. In mice, acute administration of IGF1 promotes follicle advance and increased oocyte yield. The results suggest that while superphysiological IGF1 alone advances the pace of growth among early/preantral follicles, a sustained and/or later-stage influence undermines antral follicle growth/survival or promotes premature luteinization. These findings provide a temporal framework for interpreting follicle growth/mobilization and may be useful in understanding the clinical application of human growth hormone in the context of assisted reproduction.

Excited-state intramolecular proton transfer in the kinetic-control regime.

A new series of molecules bearing a 2,11-dihydro-1H-cyclopenta[de]indeno[1,2-b]quinoline (CPIQ) chromophore with the N-HN type of intramolecular hydrogen bond are strategically designed and synthesized, among which CPIQ-OH, CPIQ-NHAc and CPIQ-NHTs in solution exhibit a single emission band with an anomalously large Stokes shift, whereas CPIQ-NH2 and CPIQ-NHMe show apparent dual-emission property. This, in combination with time-resolved spectroscopy and the computational approach, leads us to conclude that CPIQ-OH, CPIQ-NHAc and CPIQ-NHTs undergo ultrafast, highly exergonic excited-state intramolecular proton transfer (ESIPT), while a finite rate of ESIPT is observed for CPIQ-NH2 and CPIQ-NHMe with a time constant of 117 ps and 39 ps, respectively, in acetonitrile at room-temperature. Further temperature-dependent studies deduce an appreciable ESIPT barrier for CPIQ-NH2 and CPIQ-NHMe. Different from most of the barrier associated ESIPT molecules that are commonly in the thermodynamic-control regime, i.e. found in the thermal pre-equilibrium between excited normal and proton-transfer tautomer states, CPIQ-NH2 and CPIQ-NHMe cases are in the kinetic-control regime where ESIPT is irreversible with a significant barrier. The barrier is able to be tuned by the electronic properties of the -R group in the NR-H proton donor site, resulting in ratiometric fluorescence for normal versus tautomer emission.

Diversified Excited-State Relaxation Pathways of Donor-Linker-Acceptor Dyads Controlled by a Bent-to-Planar Motion of the Donor.

Herein, we introduce the cyclic 8π-electron (C8π) molecule N,N'-diaryl-dihydrodibenzo[a,c]phenazine (DPAC) as a dual-functional donor to establish a series of new donor-linker-acceptor (D-L-A) dyads DLA1-DLA5. The excited-state bent-to-planar dynamics of DPAC regulate the energy gap of the donor, while the acceptors A1-A5 are endowed with different energy gaps and HOMO/LUMO levels. As a result, the rate and efficiency of the excited-state electron transfer vs. energy transfer can be finely harnessed, which is verified via steady-state spectroscopy and time-resolved emission measurements. This comprehensive approach demonstrates, for the first time, the manifold of excited-state properties governed by bifunctional donor-based D-L-A dyads, including bent-to-planar, photoinduced electron transfer (PET) from excited donor to acceptor (oxidative-PET), fluorescence resonance energy transfer (FRET), bent-to-planar followed by electron transfer (PFET), and PET from donor to excited acceptor (reductive-PET).

Substituted benzothiophene and benzofuran derivatives as a novel class of bone morphogenetic Protein-2 upregulators: Synthesis, anti-osteoporosis efficacies in ovariectomized rats and a zebrafish model, and ADME properties.

The bone morphogenetic protein (BMP) pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. This study optimized the structure of the anti-osteoporosis compound 38 by balancing its lipophilicity and improving its stability. Twenty derivatives which were not reported in the literature were designed and synthesized. The ovariectomized rat model of osteoporosis was selected to evaluate the therapeutic effects. Compound 125 showed better therapeutic efficacy than that of 38. We verified the anti-osteoporosis activity and BMP-2 protein upregulation after treatment with 125 in a zebrafish osteoporosis model. We found that 125 improved the ADME properties, therapeutic efficacy, and pharmacokinetics of the drug. Overall, we evaluated the anti-osteoporosis effects of the compounds of this type, preliminarily determined the target patient population, verified the mechanism of action, clarified the level of toxicity, and provided preliminary ADME data. We believe that these compounds can both correct bone loss that is already occurring in patients and have broad clinical applicability.

A Facile Molecular Machine: Optically Triggered Counterion Migration by Charge Transfer of Linear Donor-π-Acceptor Phosphonium Fluorophores.

The D-π-A type phosphonium salts in which electron acceptor (A=-+ PR3 ) and donor (D=-NPh2 ) groups are linked by polarizable π-conjugated spacers show intense fluorescence that is classically ascribed to excited-state intramolecular charge transfer (ICT). Unexpectedly, salts with π=-(C6 H4 )n - and -(C10 H6 C6 H4 )- exhibit an unusual dual emission (F1 and F2 bands) in weakly polar or nonpolar solvents. Time-resolved fluorescence studies show a successive temporal evolution from the F1 to F2 emission, which can be rationalized by an ICT-driven counterion migration. Upon optically induced ICT, the counterions move from -+ PR3 to -NPh2 and back in the ground state, thus achieving an ion-transfer cycle. Increasing the solvent polarity makes the solvent stabilization dominant, and virtually stops the ion migration. Providing that either D or A has ionic character (by static ion-pair stabilization), the ICT-induced counterion migration should not be uncommon in weakly polar to nonpolar media, thereby providing a facile avenue for mimicking a photoinduced molecular machine-like motion.

Sulfur-Based Intramolecular Hydrogen-Bond: Excited-State Hydrogen-Bond On/Off Switch with Dual Room-Temperature Phosphorescence.

We report O-H----S hydrogen-bond (H-bond) formation and its excited-state intramolecular H-bond on/off reaction unveiled by room-temperature phosphorescence (RTP). In this seminal work, this phenomenon is demonstrated with 7-hydroxy-2,2-dimethyl-2,3-dihydro-1 H-indene-1-thione (DM-7HIT), which possesses a strong polar (hydroxy)-dispersive (thione) type H-bond. Upon excitation, DM-7HIT exhibits anomalous dual RTP with maxima at 550 and 685 nm. This study found that the lowest lying excited state (S1) of DM-7HIT is a sulfur nonbonding (n) to π* transition, which undergoes O-H bond flipping from S1(nπ*) to the non-H-bonded S'1(nπ*) state, followed by intersystem crossing and internal conversion to populate the T'1(nπ*) state. Fast H-bond on/off switching then takes place between T'1(nπ*) and T1(nπ*), forming a pre-equilibrium that affords both the T'1(nπ*, 685 nm) and T1(nπ*, 550 nm) RTP. The generality of the sulfur H-bond on/off switching mechanism, dubbed a molecule wiper, was rigorously evaluated with a variety of other H-bonded thiones, and these results open a new chapter in the chemistry of hydrogen bonds.

Intramolecular Phosphacyclization: Polyaromatic Phosphonium P-Heterocycles with Wide-Tuning Optical Properties.

Rationally designed cationic phospha-polyaromatic fluorophores were prepared through intramolecular cyclization of the tertiary ortho-(acene)phenylene-phosphines mediated by CuII triflate. As a result of phosphorus quaternization, heterocyclic phosphonium salts 1 c-3 c, derived from naphthalene, phenanthrene, and anthracene cores, exhibited very intense blue to green fluorescence (Φem =0.38-0.99) and high photostability in aqueous medium. The structure-emission relationship was further investigated by tailoring the electron-donating functions to the anthracene moiety to give dyes 4 c-6 c with charge-transfer character. The latter significantly decreases the emission energy to reach near-IR region. Thus, the intramolecular phosphacyclization renders an ultra-wide tuning of fluorescence from 420 nm (1 c) to 780 nm (6 c) in solution, extended to 825 nm for 6 c in the solid state with quantum efficiency of approximately 0.07. The physical behavior of these new dyes was studied spectroscopically, crystallographically, and electrochemically, whereas computational analysis was used to correlate the experimental data with molecular electronic structures. The excellent stability, water solubility, and attractive photophysical characteristics make these phosphonium heterocycles powerful tools in cell imaging.

Improvement of the Photophysical Performance of Platinum-Cyclometalated Complexes in Halogen-Bonded Adducts.

Three groups of luminescent platinum complexes [Pt(C^N)(L)(Y)] [C^N=benzothienyl-pyridine (1), bezofuryl-pyridine (2), phenyl-pyridine (3); L/Y=DMSO/Cl (a), PPh3 /Cl (b), PPh3 /CN (c)] have been probed as halogen-bond (XB) acceptors towards iodofluorobenzenes (IC6 F5 and I2 C6 F4 ). Compounds 1 a and 2 a (L/Y=DMSO/Cl) afford the adducts 1 a⋅⋅⋅I2 C6 F4 and 2 a⋅⋅⋅I2 C6 F4 , which feature I⋅⋅⋅Sbtpy /I⋅⋅⋅πbtpy and I⋅⋅⋅ODMSO /I⋅⋅⋅Cl short contacts, respectively. The phosphane-cyanide derivatives 1 c and 2 c (L/Y=PPh3 /CN) co-crystallise with both IC6 F5 and I2 C6 F4 . None of the phpy-based species 3 a-3 c participated in XB interactions. Although the native complexes are rather poor luminophores in the solid state (Φem =0.023-0.089), the adducts exhibit an up to 10-fold increase of the intensity with a minor alteration of the emission energy. The observed gain in the quantum efficiency is mainly attributed to the joint influence of non-covalent interactions (halogen/hydrogen bonding, π-π stacking), which govern the crystal-packing mode and diminish the radiationless pathways for the T1 →S0 transition by providing a rigid environment around the chromophore.

Synthesis of a novel class of substituted benzothiophene or benzofuran derivatives as BMP-2 up-regulators and evaluation of the BMP-2-up-regulating effects in vitro and the effects on glucocorticoid-induced osteoporosis in rats.

The BMP pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. To enrich our understanding of SAR and based on our previously concluded structure-effect relationship, 23 derivatives were prepared in this work. The synthesis, up-regulating activities on BMP-2 expression, and bone loss prevention efficacies of these compounds in rats with glucocorticoid-induced osteoporosis are presented. The bone histology of the tested rats assessed through light microscopy showed that compounds 1, 21, 35, and 38 significantly increased the trabecula compared with the model group, and the trabecula of the groups treated with 8a was similar to that obtained with raloxifene and alfacalcidol. The compounds exhibited potential for development as anabolic agents.

Synthesis and antiparasitic activity of new bis-arylimidamides: DB766 analogs modified in the terminal groups.

Fifteen novel bis-arylimidamide derivatives with various 6-membered (7a-c) and 5-membered (7d-o) heterocyclic rings replacing the terminal pyridyl rings of the lead compound DB766{(2,5-bis[2-i-propoxy-4-(2-pyridylimino)aminophenylfuran]}, were prepared and evaluated versus Trypanosoma cruzi, Leishmania amazonensis, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Compound 7a with pyrimidine replacing the pyridine rings showed good activity versus T. cruzi, T. brucei rhodesiense and P. falciparum (IC50 = 200 nM, 32 nM and 8.5 nM, respectively). Three compounds (7g, 7i, 7j) with thiazole replacing the pyridine rings gave low micromolar (0.17-0.3 µM) IC50 values versus L. amazonensis, however only 7g exhibited an acceptable selectivity index (SI = 27). Compounds 7a, 7j and 7m exhibited potent activity against T. brucei rhodesiense (IC50 = 12-60 nM). Ten of the 15 compounds with pyrimidine, pyrrole, thiazole and imidazole terminal units were highly active against P. falciparum (IC50 = 9-87 nM). Both pyrimidine and pyridine terminal groups are advantageous for anti-T. cruzi activity and several different heterocyclic terminal units are effective versus P. falciparum, both findings merit further investigation.

Synthesis and antitumor activity of novel 3,4-diaryl squaric acid analogs.

A series of novel 3,4-diaryl squaric acid analogs 4a-r related to combretastatin A-4 (CA4) using squaric acid as the cis-restricted linker were prepared and studied for their anticancer activity against selected human cancer cell lines. New compounds 4g, 4k, 4m, 4n, 4p, 4q and 4r exhibit strong activities against human leukemia cells with IC50 values of ≤20 nM and compounds 4k, 4n, 4p, 4q and 4r showed potent activities against a panel of human tumor cell lines. Compounds 4n and 4p arrest tumor cell cycle in G2-M phase. Computational modeling analysis suggests that the binding mechanism of compound 4n to the colchicine binding site on the microtubules is similar to that of CA4.

Substituted benzothiophene or benzofuran derivatives as a novel class of bone morphogenetic protein-2 up-regulators: synthesis, structure-activity relationships, and preventive bone loss efficacies in senescence accelerated mice (SAMP6) and ovariectomized rats.

In this work, substituted benzothiophene and benzofuran compounds were found to be a new class of potential anabolic agents by enhancing BMP-2 expression. A series of benzothiophene and benzofuran derivatives have been synthesized, and their activities of up-regulating BMP-2 and bone loss prevention efficacies in SAMP6 mice and OVX rats have been studied. Benzothiophenes 1, 3, 14, 4a, 7a, 8a, and benzofuran analogue 2 showed higher BMP-2 up-regulation rates in vitro. Compound 8a was found to significantly affect the bone formation rate of tested SAMP6 mice. Compound 1 showed an improved bone quality in SAMP6 mice and also showed activity in OVX rats. We have demonstrated that substituted benzothiophene and benzofuran derivatives, especially compounds 1 and 8a, enhance BMP-2 expression in vitro and in vivo and stimulate bone formation and trabecular connectivity restoration in vivo. The compounds represent potential leads in the development of a new class of anabolic agents.

The effect of substituted thiophene and benzothiophene derivates on PPARgamma expression and glucose metabolism.

Eighteen substituted thiophene and benzothiophene derivatives were studied for their effects on peroxisome proliferator-activated receptor gamma (PPARgamma) in HepG2 cells. Three derivatives (compounds 5, 120.97%; 15, 102.14%; and 17, 113.82%) were found to transactivate PPARgamma in vitro. By comparison, the positive control rosiglitazone (Ros) transactivated PPARgamma by 311.53%. The three compounds were studied for their effects on glucose metabolism in vivo in KK/Ay diabetic mice. In vivo, the 2-(beta-carbonyl/sulfonyl) butyryl-thiophene compounds 5 and 15 significantly decreased blood glucose levels (compounds 5, to<15.6mmol/L; 15, to<10mmol/L), improved glucose tolerance, improved impaired pancreatic islet beta-cells, and lowered serum insulin levels.