Dimethylamino Moiety Research Articles

Comparative Photophysical Study of Differently Substituted Cinnamaldehyde-Based Chalcones: From Intramolecular Charge Transfer to Fluorogenic Solvent Selectivity.

We synthesized three cinnamaldehyde-based chalcone derivatives, (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (HPD), (2E,4E)-5-(4-(dimethylamino)phenyl)-1-phenylpenta-2,4-dien-1-one (DPPD), and (2E,4E)-5-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DPHPD). The molecule HPD was totally nonfluorescent. Exclusion of a phenolic -OH moiety from HPD along with the introduction of a dimethylamino moiety in DPPD resulted in excellent excited-state charge-transfer properties in the solution phase. Interestingly, introduction of phenolic -OH and dimethylamino moieties in DPHPD resulted in solvent selectivity in the excited state. DPHDP behaved as a strong fluorophore only in carbonyl- or thiocarbonyl-containing solvents, such as dimethylsulfoxide (DMSO), dimethylformamide (DMF) and dimethylacetamide (DMAC) and showed a prominent red color under UV light. However, no emission was observed in similar carbonylated solvents, such as acetone or formamide, or in viscous medium, such as glycerol. The difference in solvent response was probed by various spectroscopic techniques and analyzed using the crystal structure of the three chalcones along with theoretical calculations. The practical utility of DPHPD was explored by detecting the percentage of water in DMSO solvent.

Use of a Redox-Responsive 4 H-Bond Ureidopyrimidone (UPy) Array to Control Polymerization in a Upy-Based Supramolecular Polymer

Ureidopyrimidinone (UPy) derivatives, introduced by Meijer and co-workers, are capable of forming dimers linked by four strong H-bonds. They have been widely used as polymer crosslinkers in self-healing supramolecular polymers and gels. While their donor-donor-acceptor-acceptor (DDAA) H-bond motif contributes to polymer stretchiness, their relatively high association constant of 106 also contributes to their ability to autonomously self-repair. This presentation shows the result of substituting a UPy with a N,N- dimethyl-p-phenylenediamine and therefore adding a redox reactive dimension to self-repair. In particular, this work involves the electrochemical investigation of UPyH (shown below) with a series of different bases, specifically pyridine and substituted pyridines. The focus is on finding the appropriate electroinactive base that facilitates both the dimer break up upon oxidation and proton transfer and dimer reformation by reduction and back proton transfer. Cyclic voltammetry (CV) scans of UPyH only, conducted in CH2Cl2 at slower scan rates, show two reversible redox waves. The first wave is of one electron height, corresponding to a two-electron transfer per dimer. At a higher oxidation potential, the second oxidation wave is one half the height of the first and then on the return scan, a slightly more negative potential is needed for reduction. At a faster scan rate, the CV response for the second wave shows that it becomes irreversible. Also, at a faster scan rate, a new reduction wave appears at a more negative peak potential than the reduction wave for the first electron transfer process. This type of CV return wave behavior for UPyH at faster scan rates was previously seen in another dimethylphenylurea redox active compound with only two H-bonding sites, UHH. In the UHH investigation, CV and spectroelectrochemical results pointed to the dimethylamino moiety being basic enough to abstract an N-H proton in the radical cation oxidation state and therefore allowing for a two electron transfer wave to give the quinoidal cation. A similar reduction wave negative of the first redox wave was seen in acetonitrile at all scan rates, while in CH2Cl2 this wave was seen only at faster scan rates. At slower scans the first oxidation remained reversible. Based upon the UHH study, interpretation of the UPyH second oxidation wave is that it correspond with a second e- transfer per redox center. Each urea-phenylenediamine N-H site in the dimer then becomes acidic enough to transfer its proton to the carbonyl oxygen on the UPyH isocytosine. This would then change the favorable binding motif of DDAA to a weaker binding motif of ADAD. In addition, a 2+ charge forms on each monomer in the dimer contributing to strong repulsive forces. This results in dimer break-up, where upon the protonated isocytosine carbonyl on each monomer is exposed to the more basic dimethylamino site on a fully reduced UPyH dimer. Proton transfer from the isocytosine to the dimethyl amino renders the fully reduced dimer electroinactive, explaining the half wave height. Thus, the overall reaction, shown in the accompanying scheme, corresponds to break up of the half the starting dimers, with two electron oxidation and deprotonation of each monomer to give two UPy+. However, the other half of the UPy’s remain dimerized in the protonated form as (HUPyH+)2. Further investigation focuses on the addition of a series of substituted pyridines as a base and their effect on dimer break up and reformation as it competes with the dimethylamino moiety on the phenylenediamine. The goal is to find an external base that will allow full oxidation and break up of all the UPyH dimers, while retaining the chemical reversibility of the process. UPy has a unique self-healing property that can be observed electrochemically as a redox couple which can be useful for supramolecular polymers. With the use of UPyH’s H-bond array and a phenylenediamine redox couple attached to the urea, this would allow H-donating of the NH urea. The main focus of this study is UPyH+ base will be used as a redox-controlled chain terminator that can control the degree of polymerization. The viscosity of the supramolecular polymers will determine if UPyH base would act as a chain terminator, and if it would be electroactive to oxidize to deactivate the polymer chain to reform a chain with the base. When the polymers reduce, UPyH would go back at its starting state by reforming with itself.

Novel D-π-A organic dyes for DSSCs based on dibenzo[b,h][1,6]naphthyridine as a π-bridge

A new series of D-π-A organic dyes bearing fused dibenzo[b,h] [1,6]naphthyridine as the conjugated π-bridge, a cyanoacrylic acid moiety as the electron acceptor/anchoring group and different electron donor groups such as trimethoxy (5a), methoxy (5b) and dimethylamino (5c), were designed and synthesized for dye-sensitized solar cells (DSSCs), for the first time. The effect of donor groups on the performance of the DSSCs was systematically investigated using optical, electrochemical, theoretical and photovoltaic methods. Compared to dyes 5a and 5b, 5c showed a broader and more red-shifted absorption spectrum due to stronger electron donating ability of dimethylamino moiety, which is beneficial for absorbing more photons and thus generating high photocurrent. As a result, the DSSC fabricated with dye 5c has the highest power conversion efficiency of 5.02% (∼60% relative to N719-based standard cell), which is greater than those obtained by 5a and 5b-sensitized solar cells (3.22% and 2.13%, respectively) under standard air mass 1.5 global (AM 1.5 G) conditions. The improved photovoltaic performance mainly came from better photocurrent, as also confirmed by IPCE measurements. These results suggest that dibenzo[b,h][1,6]naphthyridine π-bridge bearing a strong electron donor group is a promising candidate to construct effective D–π–A organic dyes for DSSCs.

Profiling of carboxyl-containing metabolites in smokers and non-smokers by stable isotope labeling combined with LC-MS/MS

Profiling of carboxyl-containing metabolites in smokers and non-smokers provides insight into the smoking-related biological events and causal relationships between exposure and adverse events. However, more comprehensive analysis of carboxyl-containing metabolites in bio-matrices with high sensitivity and accuracy is challenging. In this work, stable isotope labeling in combination with liquid chromatography-tandem mass spectrometry was used for untargeted profiling and relative quantification of carboxyl-containing metabolites in plasma of smokers and non-smokers. A pair of isotope labeling reagents, N, N-dimethylethylenediamine (DMED) and d4-DMED was used to label carboxyl-containing metabolites. Since the isotope labeled dimethylamino moieties of DMED and d4-DMED are easily fragmented and lost as characteristic neutral fragments of 45 and 49 Da, respectively, double neutral loss scans can be used to profiling of carboxyl-containing metabolites. Subsequently, based on the ion pair parameters obtained from double neutral loss scans, relative quantification method was developed. As a result, 269 carboxyl-containing metabolite candidates were discovered, and 88 metabolite candidates were found to have significant alterations between smokers and non-smokers. 7Z, 10Z-hexadecadienoic acid, myristic acid and 3β-hydroxy-5-cholestenoic acid with significant differences confirmed by standard comparison are linked to smoking related inflammation, abnormal bile acid synthesis and cholesterol metabolism.

Fungal biodegradation of the N-nitrosodimethylamine precursors venlafaxine and O-desmethylvenlafaxine in water

Antidepressant drugs such as Venlafaxine (VFX) and O-desmethylvenlafaxine (ODMVFX) are emerging contaminants that are commonly detected in aquatic environments, since conventional wastewater treatment plants are unable to completely remove them. They can be precursors of hazardous by-products, such as the carcinogenic N-nitrosodimethylamine (NDMA), generated upon water chlorination, as they contain the dimethylamino moiety, necessary for the formation of NDMA. In this study, the capability of three white rot fungi (Trametes versicolor, Ganoderma lucidum and Pleurotus ostreatus) to remove both antidepressants from water and to decrease NDMA formation potential was investigated. Furthermore, transformation by-products (TPs) generated along the treatment process were elucidated and also correlated with their NDMA formation potential.Very promising results were obtained for T. versicolor and G. lucidum, both being able to remove up to 100% of ODMVFX. In the case of VFX, which is very recalcitrant to conventional wastewater treatment, a 70% of removal was achieved by T. versicolor, along with a reduction in NDMA formation potential, thus decreasing the associated problems for human health and the environment. However, the NDMA formation potential remained practically constant during treatment with G. lucidum despite of the equally high VFX removal (70%). This difference was attributed to the generation of different TPs during both fungal treatments. For example, G. lucidum generated more ODMVFX, which actually has a higher NDMA formation potential than the parent compound itself.

Inhibition of LDL oxidation and inflammasome assembly by nitroaliphatic derivatives. Potential use as anti-inflammatory and anti-atherogenic agents

We have previously shown the antioxidant and anti-inflammatory properties of several para-substituted arylnitroalkenes. Since oxidative stress and inflammation are key processes that drive the initiation and progression of atherosclerosis, in the present work the antioxidant, anti-inflammatory and anti-atherogenic properties of an extended library of aryl-nitroaliphatic derivatives, including several newly designed nitroalkanes, was explored. The antioxidant capacity of the nitroaliphatic compounds, measured using the oxygen radical absorbance capacity assay (ORAC) showed that the p-methylthiophenyl-derivatives were about three times more effective than Trolox to prevent fluorescein oxidation, independently of the presence or the absence of the double bond next to the nitro group. The peroxyl radical scavenger capacity of the p-dimethylaminophenyl-derivatives was even higher, being the reduced form of these compounds even more active. In fact, while the antioxidant capacity of 1-dimethylamino-4-(2-nitro-1Z-ethenyl)benzene and 1-dimethylamino-4-(2-nitro-1Z-propenyl)benzene was 4.2 ± 0.1 and 5.4 ± 0.1 Trolox Eq/mol, respectively; ORAC values obtained with the ethyl and the propyl derivatives were 10 ± 1 and 13 ± 2 Trolox Eq/mol, respectively. The p-dimethylamino-derivatives, especially the nitroalkanes, were also able to prevent LDL oxidation mediated by peroxyl radicals. Oxygen consumption due to the oxidation of fatty acids was delayed in the presence of the dimethylamino substituted compounds, only the alkanes interrupted the chain of lipid oxidations decreasing the rate of oxygen consumption. Although the formation of foam cells in the presence of oxidized-LDL (oxLDL) remained unaffected, the molecules containing the dimethylamino moiety were able to decrease the expression of IL-1β in LPS/INF-γ challenged macrophages.

Chiral 2-Aminobenzimidazole as Bifunctional Catalyst in the Asymmetric Electrophilic Amination of Unprotected 3-Substituted Oxindoles

The use of readily available chiral trans-cyclohexanediamine-benzimidazole derivatives as bifunctional organocatalysts in the asymmetric electrophilic amination of unprotected 3-substituted oxindoles is presented. Different organocatalysts were evaluated; the most successful one contained a dimethylamino moiety (5). With this catalyst under optimized conditions, different oxindoles containing a wide variety of substituents at the 3-position were aminated in good yields and with good to excellent enantioselectivities using di-tert-butylazodicarboxylate as the aminating agent. The procedure proved to be also efficient for the amination of 3-substituted benzofuranones, although with moderate results. A bifunctional role of the catalyst, acting as Brønsted base and hydrogen bond donor, is proposed according to the experimental results observed.

A small bifunctional chelator that modulates Aβ42 aggregation

Multifunctional compounds that can modulate amyloid-β (Aβ) aggregation and interact with metal ions hold considerable promise as therapeutic agents for Alzheimer’s disease (AD). Using the copper-catalyzed azide-alkyne cycloaddition reaction, a novel bifunctional chelator 2-(1-(4-(dimethylamino)benzyl)-1H-1,2,3-triazol-4-yl)phenol (L1) was synthesized. L1 contains a bidentate metal-binding unit and a pendant dimethylamino moiety. The product was characterized by 1H NMR, 13C NMR, and MS. The metal-binding properties of L1 were probed by UV–vis spectroscopy to determine Cu:L stoichiometry. L1 was determined to limit Aβ aggregation at 48 h via a ThT assay. In addition, L1 complies with Lipinski’s rules and calculated logBB values for potential drug likeness and BBB permeability. These results suggest that L1 is a suitable candidate for further study as a multifunctional compound to treat AD.

Elaborating the excited state behavior of 2‐(4′‐N,N‐dimethylaminophenyl)‐imidazo[4,5‐c]pyridine coupling with methanol solvent

AbstractWe present a theoretical investigation about the excited state dynamical mechanism of 2‐(4′‐N,N‐dimethylaminophenyl)‐imidazo[4,5‐c]pyridine (DMAPIP‐c). Within the framework of density functional theory and time‐dependent density functional theory methods, we reasonably repeat the experimental electronic spectra, which further confirm the theoretical level used in this work is feasible. Given the best complex model, 3 methanol (MeOH) solvent molecules should be connected with DMAPIP‐c forming DMAPIP‐c‐MeOH complex in both ground state and excited state. Exploring the changes about bond lengths and bond angles involved in hydrogen bond wires, we find the O7‐H8···N9 one should be largely strengthened in the S1 state, which plays an important role in facilitating the excited state intermolecular proton transfer (ESIPT) process. In addition, the analyses about infrared vibrational spectra also confirm this conclusion. The redistribution about charges distinguished via frontier molecular orbitals based on the photoexcitation, we do find tendency of ESIPT reaction due to the most charges located around N9 atom in the lowest unoccupied molecular orbital. Based on constructing the potential energy curves of both S0 and S1 states, we not only confirm that the ESIPT process should firstly occur along with hydrogen bond wire O7‐H8···N9, but also find a low potential energy barrier 8.898 kcal/mol supports the ESIPT reaction in the S1 state forming DMAPIP‐c‐MeOH‐PT configuration. Subsequently, DMAPIP‐c‐MeOH‐PT could twist its dimethylamino moiety with a lower barrier 3.475 kcal/mol forming DMAPIP‐c‐MeOH‐PT‐TICT structure. Our work not only successfully explains previous experimental work but also paves the way for the further applications about DMAPIP‐c sensor in future.

The Electrochemistry of 1-Ferrocenyl-3-Phenylurea (FcUHH) in the Presence of the Diamide Guest, 1,4-Dimethylpiperizine-2,3-Dione (PZD)

Strength and directionality are the hallmark binding characteristics of molecules with multiple hydrogen bonds. This is important in the area of molecular recognition and supramolecular construction. When coupled to a redox center, oxidation or reduction can affect the electrostatic property of hydrogen bonds to either strengthen or weaken hydrogen bonding and thus allow for more control over this type of binding. A good example of strengthening hydrogen bonds can be seen in the use of a bi-substituted urea. Previous investigations from our lab showed that as a substrate, with its two side-by-side NH hydrogen donor binding sites (DD), N,N'-diphenylurea forms two, linear, primary hydrogen bonds with both dicarbonyl oxygens on a hydrogen bond acceptor (AA), 9,10-phenanthraquinone as shown below. In addition to the primary hydrogen bonds the DD-AA motif provides secondary hydrogen bond forces that enhanced the overall binding strength. Upon reduction of the 9,10-phenanthraquinone in the presence of the diphenylurea, both primary and secondary binding forces from the DD-AA motif stabilize the radical anion causing the half-wave potential to shift to more positive values with more urea added. With the addition of a dimethylamino moiety onto one of the phenyl substituents to form a phenylenediamine redox center, the urea substrate was converted to a redox anion receptor, 1-phenyl-3-(4-dimethylamino)phenyl urea, (UHH). This meant that the phenylenediamine-urea N-H site could be perturbed upon electron transfer. The first oxidation forms a radical cation where delocalization of the positive charge in the redox center could also strengthen hydrogen bonding to the N-H, but upon a second electron transfer, the delocalization of two positive charges forms a very acidic NH site that could easily undergo proton transfer. Initial CV studies with UHH conducted in a limited potential window and in the presence of 1,4-dimethylpiperizine-2,3-dione (PZD), a diamide that has two carbonyl oxygens structurally compatible to the two urea N-H’s, showed a single, reversible oxidation wave shifting in the negative direction with increasing amounts of PZD, indicating an increase in binding strength. Upon expansion of the potential window a second oxidation wave is seen that also shifts in the negative direction with increasing amounts of PZD but its current height is comparatively smaller and the wave becomes irreversible which can not be explained by hydrogen bonding only. CV investigations of UHH alone revealed that what was thought to be a simple one electron transfer process, is a much more complicated two electron, one proton transfer. It turns out that the dimethylamino moiety on a fully reduced UHH is basic enough to remove a proton from another singly oxidized UHH allowing for an immediate second electron transfer at the same potential. Ultimately, a fully oxidized phenylenediamine redox center will not enhance binding strength due to proton transfer. Our new strategy and the subject of this poster presentation, is the replacement of the phenylenediamine redox center with a ferrocene redox center (FcUHH). This change limits the oxidation to a single electron transfer process without a basic site for proton transfer. Initial CV experiments of FcUHH in methylene chloride show a reversible, one electron oxidation as expected. With the addition of PZD, small negative shifts in the halfwave potential are seen, consistent with stronger H-bonding to the oxidized form. Figure 1

Effect of Added Bases on the Redox-Responsive Dimerization of a 4 H-Bond Array Containing a Phenylenediamine Redox Couple

Ureidopyrimidinone (UPy) derivatives, introduced by Meijer and co-workers, are capable of forming dimers linked by four strong H-bonds. They have been widely used as polymer crosslinkers in self-healing supramolecular polymers and gels. While their donor-donor-acceptor-acceptor (DDAA) H-bond motif contributes to polymer stretchiness, their relatively high association constant of 106 also contributes to their ability to autonomously self-repair. This presentation shows the result of substituting a UPy with a N,N- dimethyl-p-phenylenediamine and therefore adding a redox reactive dimension to self-repair. In particular, this work involves the electrochemical investigation of UPyH (shown below) with a series of different bases, specifically pyridine and substituted pyridines. The focus is on finding the appropriate electroinactive base that facilitates both the dimer break up upon oxidation and proton transfer and dimer reformation by reduction and back proton transfer. Cyclic voltammetry (CV) scans of UPyH only, conducted in CH2Cl2 at slower scan rates, show two reversible redox waves. The first wave is of one electron height, corresponding to a two-electron transfer per dimer. The second oxidation wave at more positive potential is one half the height of the first and less reversible than the first. At a faster scan rate, the second wave becomes irreversible and a new reduction wave appears at a more negative potential than the reduction wave for the first electron transfer process. This type of CV return wave behavior for UPyH at faster scan rates was previously seen in another dimethylphenylurea redox active compound with only two H-bonding sites, UHH. In the UHH investigation, CV and spectroelectrochemical results pointed to the dimethylamino moiety being basic enough to abstract an N-H proton in the radical cation oxidation state and therefore allowing for a two electron transfer wave to give the quinoidal cation. A similar reduction wave negative of the first redox wave was seen in acetonitrile at all scan rates, while in CH2Cl2 this wave was seen only at faster scan rates. At slower scans the first oxidation remained reversible. Based upon the UHH study, interpretation of the UPyH second oxidation wave is that it correspond with a second e- transfer per redox center. Each urea-phenylenediamine N-H site in the dimer then becomes acidic enough to transfer its proton to the carbonyl oxygen on the UPyH isocytosine. This would then change the favorable binding motif of DDAA to a weaker binding motif of ADAD. In addition, a 2+ charge forms on each monomer in the dimer contributing to strong repulsive forces. This results in dimer break-up, where upon the protonated isocytosine carbonyl on each monomer is exposed to the more basic dimethylamino site on a fully reduced UPyH dimer. Proton transfer from the isocytosine to the dimethyl amino renders the fully reduced dimer electroinactive, explaining the half wave height. Thus, the overall reaction, shown in the accompanying scheme, corresponds to break up of the half the starting dimers, with two electron oxidation and deprotonation of each monomer to give two UPy+. However, the other half of the UPy’s remain dimerized in the protonated form as (HUPyH+)2. Further investigation focuses on the addition of a series of substituted pyridines as a base and their effect on dimer break up and reformation as the added base competes with the dimethylamino moiety on the phenylenediamine. The goal is to find an external base that will allow full oxidation and break up of all the UPyH dimers, while retaining the chemical reversibility of the process. Figure 1

A new ratiometric two-photon fluorescent probe for imaging of lysosomes in living cells and tissues

Intracellular pH plays a pivotal role in various biological processes. Herein, we adopted the through bond energy transfer (TBET) strategy to design a unique type of ratiometric two-photon fluorescent probe for imaging of lysosomal pH in live cells and tissues, termed Np-Rh-Lys. Specifically, a two-photon fluorophore (D-π-A-structured naphthalimide derivative) and a rhodamine B fluorophore were directly connected, and dimethylamino moiety served as a lysosomal targeting-group. The experiments demonstrate new probe Np-Rh-Lys was a reliable and specific probe for labeling lysosomes in living cells with two well-resolved emission peaks separated by 80 nm, and which showed high ratiometric imaging resolution and deep-tissue imaging depth over 180 μm, we thus may expect the new platform prompt the development of a wide variety of ratiometric two-photon fluorescent probes application in biological systems.

Solid state emission and mechanochromic luminescence of boron 2-(2′-pyridyl)imidazole complexes

A series of boron 2-(2′-pyridyl)imidazole complexes were found to exhibit solid state emission and mechanochromic properties, meanwhile the terminal substituent play an important role in their properties. When the boron-difluoride dye bears dimethylamino moieties which can freely rotate, it emits poorly in most organic solvents and in the amorphous powder, but visible emission was observed in the crystalline state. Comparatively, the dyes comprising cyclohexylamino and diphenylamino substitutes show higher fluorescent efficiencies both in solutions and in the solid powder state, due to the larger steric hindrance. However, mechanochromism was observed only for the dyes bearing dimethylamino and diphenylamino moieties. According to XRD analysis, the transition of crystalline to amorphous state by grinding is ascribed to be the driving force for the mechanochromic character, and the flexibility of cyclohexylamino groups makes the dye inclined to be in amorphous state and non-responsive to mechanical force.

Two Sensitive Fluorescent BOPIM Probes with Tunable TICT Character for Low-Level Water Detection in Organic Solvents.

Two novel Boron-fluorine derivatives bearing dimethylamino moieties, BOPIM-1 and BOPIM-2, were proposed as sensitive fluorescent sensors for low-level water quantification in organic solvents. Two BOPIMs exhibit typical phenomenon for an emission from a twisted intra-molecular charge transfer (TICT) state, the emission red shift and intensity weakening with solvent polarity. Introduction of trace amount of water to solvent resulted in fluorescent quenching, accompanied by the red shift of the emission, which was attributed to the formation of TICT excitation of BOPIMs by hydrolysis. A quantification method to detect water content was developed, described by a linear equation lg(I/I(0)) vs. lg φ(w) in the range of φ(w) (volume fraction of water) 0.001~0.01, 0.01~0.1, respectively. The experiment results of determination of water in real 1, 4-dioxane (Diox) samples proved that this method can be used in practical application.

Cytotoxic, Antiproliferative and Apoptotic Effects of New Benzimidazole Derivatives on A549 Lung Carcinoma and C6 Glioma Cell Lines.

Benzimidazole ring is a versatile structure which has been extensively utilized in medicinal chemistry. Since we are working on 1,2-disubstutited benzimidazoles, we have reported new antitumor active derivatives. As a continuation to our previous work, we have synthesized a new series of 1-(2-aryl-2-oxoethyl)-2-[(N,Ndimethylamino/pyrrolidinyl/piperidinyl)thiocarbamoyl] benzimidazole derivatives. Anticancer activity of the compounds was evaluated using MTT assay, BrdU assay and flow cytometric analysis on A549 human lung carcinoma and C6 rat glioma cell lines. Compounds bearing dimethylamino moiety exhibited higher antitumor activity.

Abstract 1665: Design, synthesis, biological evaluation of cyclopenta[d]pyrimidines as antitubulin agents and discovery of N-(4-methylthiophenyl) and N-(4-dimethylaminophenyl) substituted N,2-dimethyl-cyclopenta[d]pyrimidines as long acting and poten

Abstract Compounds that bind to the colchicine site of microtubules have promising antitumor potential. Some of these agents also possess the ability to overcome multiple drug resistance mechanisms, including those mediated by the expression of P-glycoprotein (Pgp) or expression of the tubulin β-III isotype. We have reported that compounds 1 and 2 were potent antiproliferative agents that bind to the colchicine site of tubulin. The previous structure-activity relationship studies of cyclopenta[d]pyrimidine based antitubulin agents demonstrated the importance of the para-methoxyphenyl moiety for antiproliferative activity. However, the literature suggests that the major metabolism of the methoxyphenyl moiety was likely O-demethylation. In order to increase the potency and in vivo stability of 1, we focused our attention on the variation of the para-methoxy aniline moiety. Compound 3 with a 4′-methylthiophenyl substitution was designed to decrease potential metabolic demethylation. This S-methyl analog was a potent inhibitor of proliferation with an IC50 of 4.6 ± 0.5 nM in MDA-MB-435 cells. The possible sulfoxide metabolite, 4 was synthesized and had an IC50 = 7.9 ± 0.5 nM. Each of these depolymerized microtubules. In addition, the 4′-dimethylamino moiety compound 5 also demonstrated potent antitubulin and antiproliferative activity (MDA-MB-435: IC50 = 8.2 ± 0.6 nM). The possible N-demethylated metabolite of 5, para-methylamino 6 was also a highly potent antiproliferative agent (MDA-MB-435: IC50 = 20 ± 1.9 nM). The parent compounds 3 and 5, as well as their probable metabolites 4 and 6, inhibited the binding of [3H]colchicine to tubulin, which showed that these compounds bind to the colchicine site. The potent antiproliferative activities of the parent compounds and the potential metabolites of compounds 3 and 5 suggest the utility of 3 and 5 as long acting, potent antimitotic agents. Finally, the in vivo efficacy of the S-methyl analog 2 was demonstrated against MDA-MB-435 triple negative breast cancer murine xenograft model, indicating the potential utility of these analogs as antitumor agents. Citation Format: Aleem Gangjee, Weiguo Xiang, Susan L. Mooberry, Ernest Hamel. Design, synthesis, biological evaluation of cyclopenta[d]pyrimidines as antitubulin agents and discovery of N-(4-methylthiophenyl) and N-(4-dimethylaminophenyl) substituted N,2-dimethyl-cyclopenta[d]pyrimidines as long acting and poten [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1665. doi:10.1158/1538-7445.AM2015-1665

1,3,5-Triarylpyrazolines — pH-driven off-on-off molecular logic devices based on a “receptor1-fluorophore-spacer-receptor2” format with internal charge transfer (ICT) and photoinduced electron transfer (PET) mechanisms

The excited state photophysical properties of the 1,3,5-triarylpyrazolines 1–4 were studied in methanol and 1:1 (v/v) methanol–water, as well as 1:4 (v/v) methanol–water and water by fluorescence spectroscopy. The molecules 2–4 incorporate a “receptor1-fluorophore-spacer-receptor2” format while 1 is a reference compound based on a “fluorophore-receptor1” design. The molecular probes operate according to photoinduced electron transfer (PET) and internal charge transfer (ICT) processes. At basic and neutral pHs, 2–4 are essentially nonfluorescent due to PET from the electron-donating dimethylamino moiety appended on the 5-phenyl ring to the excited state of the 1,3,5-triarylpyrazoline fluorophore. At proton concentrations of 10−3 mol/L, the dimethylamino unit is protonated resulting in a strong blue fluorescence about 460 nm with significant quantum yields up to 0.54. At acid concentrations above 10−2 mol/L, fluorescence quenching is observed by an ICT mechanism due to protonation of the pyrazoline chromophore. Symmetrical off-on-off fluorescence–pH profiles are observed, spanning six log units with a narrow on window within three pH units. Hence, 2–4 are novel examples of ternary photonic pH sensing molecular devices.

A Hyperbranched Conjugated Polymer as the Cathode Interlayer for High‐Performance Polymer Solar Cells

An alcohol-soluble hyperbranched conjugated polymer HBPFN with a dimethylamino moiety is synthesized and used as a cathode interlayer. A PCE of 7.7% is obtained for PBDTTT-C-T/PC71 BM based solar cells. No obvious interfacial dipole is found at the interface between the active layer and HBPFN however, an interfacial dipole with the cathode could be one of the reasons for the enhanced performance.

Complexation Enhanced Excited‐State Deactivation by Lithium Ion Coordination to a Borondipyrromethene (Bodipy) Donor–Bridge–Acceptor Dyad

AbstractA donor–acceptor dyad was prepared comprised of a borondipyrromethene (Bodipy) chromophore as the acceptor and a dimethylamino moiety as the donor. The two groups are separated by a 2,2′‐biphenol moiety. The excited state of the Bodipy is efficiently quenched by electron transfer involving donation from the dimethyl amino group. The rate constant for forward electron transfer in DMF was measured to be ca. 2 × 1010 s–1. The charge recombination process is ultrafast. Titration of aliquots of LiClO4 to a DMF solution of the dyad resulted in alterations to the absorption spectrum associated with the 2,2′‐biphenol unit. Changes were modelled as Li+ ions bound to the oxygen atoms of the 2,2′‐biphenol to produce 1:1 (Li+/ligand) and 2:1 (Li+/ligand) complexes. The rate constant for excited state quenching is enhanced upon lithium ion binding.

Crystalline solid responsive to mechanical and acidic stimuli: Boron–fluorine derivative with TICT characteristic

Mechanochromism is found for a novel Boron-fluorine derivative bearing dimethylamino moieties (BOPIM-dma). The title compound shows weak or no fluorescence in organic solvents due to twisted intramolecular charge transfer (TICT), which induces energy lost via non-irradiation decay. However, intense fluorescence was observed in crystalline solid, obtained by recrystallization from organic solvents. Grinding the polycrystals of BOPIM-dma into amorphous solid induces red-shift of absorption and fluorescence quenching, which could be recovered by recrystallization. Moreover, the absorption and fluorescence of the crystalline solid could also be reversibly tuned by acidic and basic vapor.