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The aggregation properties of semaglutide, a lipidated peptide drug agonist of the Glucagon-like peptide 1 receptor recently approved for the treatment of type 2 diabetes, have been investigated by spectroscopic techniques (UV-Vis absorption, steady-state and time-resolved fluorescence, and electronic circular dichroism) and molecular dynamics simulations. We show that in the micromolar concentration region, in aqueous solution, semaglutide is present as monomeric and dimeric species, with a characteristic monomer-to-dimer transition occurring at around 20 µM. The lipid chain stabilizes a globular morphology of the monomer and dimer species, giving rise to a locally well-defined polar outer surface where the lipid and peptide portions are packed to each other. At very long times, these peptide clusters nucleate the growth of larger aggregates characterized by blue luminescence and a ß-sheet arrangement of the peptide chains. The understanding of the oligomerization and aggregation potential of peptide candidates is key for the development of long acting and stable drugs.
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Diabetes Mellitus Tipo 2 , Simulación de Dinámica Molecular , Péptidos Similares al Glucagón , Humanos , PéptidosRESUMEN
INTRODUCTION: Intrasacral meningoceles are cysts associated with herniating arachnoid with no nerve root within due to an area of weakness of the dura mater. They are thought to be congenital, but they are usually not symptomatic until adulthood. Surgical treatment is generally indicated in the presence of symptoms. METHODS: We selected cases belonging to the IB category of Nabors et al.'s classification who underwent surgery between 2008 and 2021 at Giannina Gaslini Hospital. Exclusion criteria were prior history of trauma, infections, or operations. Patients' clinical details, associated conditions, surgical techniques, peri- and postoperative complications, and outcomes were collected retrospectively from clinical charts. We compared our series to literature: keywords "intrasacral meningocele" were used on the search engine MEDLINE - Pubmed. RESULTS: We identified 23 cases: 5 of the 14 symptomatic patients had a complete resolution, and 5 had a substantial clinical improvement after surgery. Cyst recurrence and major postoperative complication occurred in none. Among 59 articles considered for evaluation, 50 were excluded and remaining 9 articles underwent full-text analysis. DISCUSSION AND CONCLUSION: The pathogenesis of instrasacral meningoceles is still not completely understood and the spectrum of symptoms is wide. A posterior surgical approach with sacral laminectomy is preferred, although in selected cases it is possible to perform a supplemental anterior approach (sometimes endoscopic). In our surgical series, the largest one published in the literature, a good clinical outcome was achieved in most patients with no cyst's recurrence, pointing out the importance of surgical interruption of communication between cyst and subdural space.
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Quistes Aracnoideos , Quistes , Meningocele , Humanos , Adulto , Meningocele/diagnóstico , Meningocele/cirugía , Estudios Retrospectivos , Laminectomía , Quistes/cirugía , Endoscopía , Quistes Aracnoideos/cirugíaRESUMEN
A novel method to build bicomponent peptide self-assembled monolayers (SAMs) has been developed, by exploiting helix···helix macrodipole interactions. In this work, a peptide-based self-assembled monolayer composed of two helical peptides was immobilized on a gold surface. Specifically, a pyrene-containing octapeptide, devoid of any sulfur atom (A8Pyr), and a hexapeptide, functionalized at the N-terminus with (S,R) lipoic acid, for binding to gold substrates (SSA4WA) via a Au-S linkage, have been employed. Both peptides investigated attain a helical structure, because they are almost exclusively formed by strongly folding inducer C(α)-tetrasubstituted α-amino acids. We demonstrate that the two peptides generate a stable supramolecular nanostructure (a densely packed bicomponent peptide monolayer), where A8Pyr is incorporated into the SSA4WA palisade by exploiting helix···helix macrodipole interactions. The presence of both peptides on the gold surface was investigated by spectroscopic and electrochemical techniques, while the morphology of the monolayer was analyzed by ultra high-vacuum scanning tunnelling microscopy. The composition of the bicomponent SAM on the surface was studied by a combination of electrochemical and spectroscopic techniques. In particular, the amount of Au-S linkages from the sulfur-containing peptides was quantified from reductive desorption of the peptide-based SAM, while the amount of A8Pyr was estimated by fluorescence spectroscopy. The antiparallel orientation of the A8Pyr and SSA4WA peptide chains minimizes the interaction energy between the helix dipoles, suggesting that this kind of electrostatic phenomenon is the driving force that stabilizes the bicomponent SAM.
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Nanoestructuras/química , Péptidos/química , Oro/química , Sustancias Macromoleculares/síntesis química , Sustancias Macromoleculares/química , Membranas Artificiales , Modelos Moleculares , Conformación Molecular , Péptidos/síntesis químicaRESUMEN
We show that Cu metal nanoparticle-multiwall carbon nanotube (MWCNT) assemblies can act as a new hybrid photoactive layer in photo-electrochemical devices. The carbon nanotube (CNT) composites were formed by a controlled thermal deposition of copper which produced crystalline metal nanoparticles localized on the carbon tube outer walls. The photoresponse evaluated in terms of IPCE (incident photon-to-charge carrier generation efficiency) varied for different sized-Cu-MWCNT samples across all the visible and near ultraviolet photon energy range with respect to the response of bare MWCNTs. In the case of 0.2 nm Cu nominal thickness, the IPCE increased, reaching 15%, a value 2.5 times higher than that measured for bare MWCNTs. As the Cu nominal coverage thickened, the IPCE started to decrease and become totally ineffective after 1 nm deposited Cu. The IPCE increase found was interpreted as being the result of a remarkable charge transfer between the Cu metal nanoparticles and the CNTs due to the formation of a strong ionic bond at their interface. The results obtained prove that the metal nanoparticle-CNT composites have optical, electrical and structural properties that can be applied in a variety of nanoscale architectures for novel photo-electrochemical devices.
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In this paper we illustrate a simple method for the production of multiwall carbon nanotubes thin films decorated with copper metal nanoparticles. The structural information obtained from the transmission electron microscopy study performed on samples differing in the quantity of deposited Copper was linked to the opto-electronic properties evaluated with photo-electrochemical measurements. The photo-response evaluated in terms of incident photon-to-charge carrier generation efficiency varied for different sized-Cu-multiwall carbon nanotubes samples across all the visible and near-ultraviolet photon energy range with respect to the response of bare carbon tubes. The photo-response from the sample covered with of 0.5 nm Cu nominal thickness, reached 10.2%, a value 2 times higher than that measured for bare carbon tubes of 5.9%. While this value decreased to 2.8% when the Cu nominal coverage thickened up to 3 nm. The increase in the photo-response found was interpreted as being the result of a remarkable charge transfer between the Cu metal nanoparticles and the carbon atoms in the tube due to the formation of a strong ionic bond at their interface. The results obtained prove that the metal nanoparticle-carbon nanotube composites have optical, electrical and structural properties that can be applied in a variety of nanoscale architectures for novel photo-electrochemical devices.
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Peptide-induced vesicle leakage is a common experimental test for the membrane-perturbing activity of antimicrobial peptides. The leakage kinetics is usually very slow, requiring minutes to hours for complete release of vesicle contents, and exhibits a biphasic behavior. We report here that, in the case of the peptaibol trichogin GA IV, all processes involved in peptide-membrane interaction, such as peptide-membrane association, peptide aggregation, and peptide translocation, take place on a timescale much shorter than the leakage kinetics. On the basis of these findings, we propose a stochastic model in which the leakage kinetics is determined by the discrete nature of a vesicle suspension: peptides are continuously exchanging among vesicles, producing significant fluctuations over time in the number of peptide molecules bound to each vesicle, and in the formation of pores. According to this model, the fast initial leakage is caused by vesicles that contain at least one pore after the peptides are randomly distributed among the liposomes, whereas the slower release is associated with the time needed to occasionally reach in an intact vesicle the critical number of bound peptides necessary for pore formation. Fluctuations due to peptide exchange among vesicles therefore represent the rate-limiting step of such a slow mechanism.
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Péptidos Catiónicos Antimicrobianos/farmacología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Liposomas Unilamelares/metabolismo , Secuencia de Aminoácidos , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/metabolismo , Cinética , Modelos Biológicos , Transporte de Proteínas , Procesos Estocásticos , TermodinámicaRESUMEN
Thymidine phosphorylase (TP) is an enzyme that is up-regulated in a wide variety of solid tumors, including breast and colorectal cancers. It is involved in tumor growth and metastasis, for this reason it is one of the key enzyme to be inhibited, in an attempt to prevent tumor proliferation. However, it also plays an active role in cancer treatment, through its contribution in the conversion of the anti-cancer drug 5-fluorouracil (5-FU) to an irreversible inhibitor of thymidylate synthase (TS), responsible of the inhibition of the DNA synthesis. In this work, the intrinsic TP fluorescence has been investigated for the first time and exploited to study TP binding affinity for the unsubstituted 5-FU and for two 5-FU derivatives, designed to expose this molecule on liposomal membranes. These molecules were obtained by functionalizing the nitrogen atom with a chain consisting of six (1) or seven (2) units of glycol, linked to an alkyl moiety of 12 carbon atoms. Derivatives (1) and (2) exhibited an affinity for TP in the micromolar range, 10 times higher than the parent compound, irrespective of the length of the polyoxyethylenic spacer. This high affinity was maintained also when the compounds were anchored in liposomal membranes. Experimental results were supported by molecular dynamics simulations and docking calculations, supporting a feasible application of the designed supramolecular lipid structure in selective targeting of TP, to be potentially used as a drug delivery system or sensor device.
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Antimetabolitos Antineoplásicos/metabolismo , Biología Computacional/métodos , Fluorescencia , Fluorouracilo/metabolismo , Liposomas/química , Fosfolípidos/metabolismo , Timidina Fosforilasa/metabolismo , Antimetabolitos Antineoplásicos/química , Sitios de Unión , Fluorouracilo/química , Humanos , Liposomas/metabolismo , Fosfolípidos/química , Timidina Fosforilasa/químicaRESUMEN
Tetraferrocenylporphyrins (TFcPs) are a class of compounds where the porphyrin macrocycle is functionalized with a ferrocenyl group at each of the four meso positions. TFcPs exhibit interesting electrochemical properties, mostly due to electronic communication between the ferrocenyl substituents and the porphyrin core. This leads to their capability to release and accept multiple electrons at distinct potentials through reversible and well distinguished processes. Synthesis of substituted-tetraferrocenylporphyrins containing a carboxylic acid functionality allowed to prepare well packed thin layers of TFcP on ITO electrodes using different deposition techniques. In this context, self-assembled monolayers (SAMs) and Langmuir-Blodgett mono- and multilayers (LBs) of TFcPs have been prepared on ITO surfaces. TFcP-functionalized ITO electrodes showed very high stability, and their application in photocatalytic oxygen activation has been tested.
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We present a combined spectroscopic and computational approach aimed to elucidate the mechanism of formation and activity of etoposide nanoaggregates upon release from dextran-etoposide conjugates. Etoposide is an anticancer drug that inhibits cell growth by blocking Topoisomerase II, the key enzyme involved in re-ligation of the DNA chains during the replication process. In silico and spectroscopic analysis indicate that released etoposide nanoaggregates have a different structure, stability, and bioactivity, which depend on the pH experienced during the release. Molecular dynamics simulation and in silico docking of etoposide dimers suggest that the aggregation phenomena inhibit etoposide bioactivity, yet without drastically preventing Topoisomerase II binding. We correlated the diminished cytotoxic activity exerted by dextran-etoposide conjugates on the A549 lung cancer cells, compared to the free drug, to the formation and stability of drug nanoaggregates.
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The UV dynamic fluorescence and CD of several Pseudomonas aeruginosa azurins bearing single amino acid mutation have been studied. Two classes of mutants were examined. In the first class, two hydrophobic residues in the core of the protein, Ile 7 and Phe 110, nearest to the azurin single tryptophan Trp 48, were substituted by a serine (mutants 17S and F110S). In the second class, two residues in the outer sphere of the copper ligand field were changed, obtaining the following mutants: M44K, H35F, H35L, and H35Q. All these proteins showed two fluorescence lifetimes in the copper-containing form, but only one in the copper-free form. The lifetime of the latter derivatives was different from either those of the metal-bound samples, definitely ruling out the presence of apo-like species in the holo protein. Copper-free 17S and F110S showed a more complex fluorescence decay profile requiring a distribution of lifetimes rather than a single lifetime. Holo F110S was also better fitted, in the limit of confidence, with two distributions rather than a pair of lifetimes. Time-resolved anisotropy of these two mutants as well as of wild-type (wt) protein showed two components (rotational times for wt < or = 200 ps and 7 ns, respectively). These components were not affected significantly by copper removal in the case of wt protein. Instead, the short rotational component of the mutants dropped dramatically to values near zero, indicating a much greater mobility of the tryptophanyl residue in the mutant apo azurins. These data were supported by CD measurements showing a small effect of the copper presence in the region below 250 nm, i.e., in the secondary structure, but almost a collapse of the aromatic asymmetry at 270-295 nm related to a relaxation of the structural constraint around the tryptophan. Altogether these data show that copper does not play a structural role in wt azurin, whereas it is crucial in the stabilization of 17S and F110S mutants. Furthermore, although the metal site geometry is rigidly kept in wt apo-azurin, it regains the native form only in the presence of the metal in the "core" mutants. This finding is important for the theory of entatic states in metalloproteins (Williams RJP, 1995, Eur J Biochem 234:363-381).
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Azurina/química , Pseudomonas aeruginosa/química , Azurina/genética , Dicroismo Circular , Polarización de Fluorescencia , Mutagénesis Sitio-DirigidaRESUMEN
Polymeric ligands, such as 2-substituted pentanedioic acid (2), 2-substituted propanoic acid (3), and deoxylactit-1-yl (4) derivatives of chitosan (1), were used to prepare copper complexes that are widely soluble in aqueous solution. EPR results (100 K) show that all association complexes basically have a tetragonal symmetry. Visible CD spectra suggest, however, that the order of increasing departure from this geometry is Cu-(1) approximately Cu-(3) less than Cu-(2) less than or equal to Cu-(4), the lack of sterically constraining side-chains in (1) and (3) allowing a more symmetric arrangement of ligands around the central metal ion. Results on the catalytic activity of the association complexes for air oxidation of catechol derivatives are also presented.
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Quitina/análogos & derivados , Cobre/química , Catálisis , Quelantes , Quitina/química , Quitina/metabolismo , Quitosano , Dicroismo Circular , Cobre/metabolismo , Espectroscopía de Resonancia por Spin del Electrón , Epinefrina/metabolismo , Estructura Molecular , Oxidación-Reducción , Solubilidad , SolucionesRESUMEN
Association complexes between iron(III) or copper(II) ions and deoxylactit-1-yl (1), 2-substituted pentanedioic acid (2), or 2-substituted propanoic acid (3) derivatives of chitosan were prepared and characterized by thermodynamic and spectroscopic measurements. Complex solutions did not show any precipitate or even opalescence, owing to the hydrolysis of free metal ions, within a wide range of [Me(n+)]/[P] molar ratio, even at a pH as high as 10.5 (Me(n+) = Fe3+ or Cu2+). Both equilibrium dialysis and Job plot experiments suggest that the functional groups in each monomeric residue are an effective site of binding for one metal ion. Reduction potentials, as obtained by cyclic voltammetric measurements, indicate that (i) coordination of the aforementioned polymeric ligands to Cu2+ ions stabilizes the oxidized species, and (ii) iron complexes have an oxidation power definitely higher than that of the corresponding copper compounds. Electron paramagnetic resonances (100 or 6 K) and Mössbauer (r.t.) spectra suggest that the order of increasing distortion from idealized geometry is Me(n+)-chitosan approximately Me(n+)-(3) < Me(n+)-(2) < or = Me(n+)-(1). These results are discussed briefly in the light of a few general considerations concerning the structural features of association complexes between macromolecules and transition metal ions.
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Quitina/análogos & derivados , Cobre/química , Compuestos Férricos/química , Quitina/química , Quitina/metabolismo , Quitosano , Cobre/metabolismo , Espectroscopía de Resonancia por Spin del Electrón , Compuestos Férricos/metabolismo , Concentración de Iones de Hidrógeno , Iones , Espectroscopía de Mossbauer , TermodinámicaRESUMEN
The solution properties and conformational features of 2-substituted propanoic acid (I) and 2-substituted pentanedioic acid (II) derivatives of chitosan were investigated over a wide range of pH by potentiometric, optical and chiroptical measurements, and by theoretical conformational analysis. No significant change is observed in the solution properties of I upon pH variations, in agreement with computational results showing that the conformational features of the polymer do not vary with respect to the charge state of the ionizable groups. In contrast, spectroscopic titration and preliminary 1H-n.m.r. data indicate that conformational equilibria in II are pH-dependent. Consistently, computed models show that both the charge state of the ionizable groups and the chirality of the carbon atom in the side chain control the structural features of the polymer.
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Quitina/análogos & derivados , Absorción , Secuencia de Carbohidratos , Quitina/química , Quitosano , Dicroismo Circular , Concentración de Iones de Hidrógeno , Conformación Molecular , Datos de Secuencia Molecular , Soluciones , Análisis EspectralRESUMEN
The aggregation propensity of helical oligopeptides formed exclusively by the conformationally constrained α-aminoisobutyric acid (Aib or U in a three- or single-letter code, respectively) was studied in methanol and methanol/water solutions by spectroscopic methods (UV-vis absorption, steady-state and time-resolved fluorescence, and FT-IR absorption) and atomic force microscopy (AFM) imaging. The peptides investigated have the general formula UnN, where n = 6, 12, and 15 and N stands for a naphthyl chromophore introduced with the dual aim to serve as a spectroscopic probe and to analyze the effect of an extended aromatic group on the aggregation process. Experiments showed that the aggregation propensity in (70/30)v/v and (50/50)v/v methanol/water solutions increases with increasing the length of the peptide chain, i.e., U6N < U12N < U15N. When the peptides are immobilized on mica as a dried film, the interplay of aromatic-aromatic and interhelix interactions, the latter becoming more and more important with the elongation of the peptide chain, governs the morphology of the resulting mesoscopic aggregates. AFM imaging revealed the formation of globular or fibrillar structures, the predominance of which is controlled by the helix length of the peptide building block.
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Oligopéptidos/química , Ácidos Aminoisobutíricos/química , Metanol/química , Modelos Moleculares , Oligopéptidos/síntesis química , Tamaño de la Partícula , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta , Propiedades de Superficie , Factores de Tiempo , Agua/químicaRESUMEN
The self-assembly of a peptide based on a sequence from the amyloid beta peptide but incorporating the non-natural amino acid beta-2-thienylalanine (2-Thi) has been investigated in aqueous and methanol solutions. The peptide AAKLVFF was used as a design motif, replacing the phenylalanine residues (F) with 2-Thi units to yield (2-Thi)(2-Thi)VLKAA. The 2-Thi residues are expected to confer interesting electronic properties due to charge delocalization and pi-stacking. The peptide is shown to form beta-sheet-rich amyloid fibrils with a twisted morphology, in both water and methanol solutions at sufficiently high concentration. The formation of a self-assembling hydrogel is observed at high concentration. Detailed molecular modeling using molecular dynamics methods was performed using NOE constraints provided by 2D-NMR experiments. The conformational and charge properties of 2-Thi were modeled using quantum mechanical methods, and found to be similar to those previously reported for the beta-3-thienylalanine analogue. The molecular dynamics simulations reveal well-defined folded structures (turn-like) in dilute aqueous solution, driven by self-assembly of the hydrophobic aromatic units, with charged lysine groups exposed to water.
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Alanina/análogos & derivados , Péptidos beta-Amiloides/química , Péptidos/química , Estructura Secundaria de Proteína , Alanina/química , Secuencia de Aminoácidos , Péptidos beta-Amiloides/genética , Dicroismo Circular , Microscopía por Crioelectrón , Hidrogeles/química , Microscopía de Fuerza Atómica , Modelos Moleculares , Simulación de Dinámica Molecular , Estructura Molecular , Péptidos/genética , Dispersión del Ángulo Pequeño , Espectrometría de Fluorescencia , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
A series of pseudopeptides, containing two fluorophores, such as naphthalene (N) and indole (I), and exhibiting interesting biological activity as tachykinin receptor antagonists, were investigated by electronic absorption, CD and steady-state fluorescence experiments. In polar solvents (e.g. methanol), bioactivity is coupled with a stacked, charge-separated complex between I and N, the amount of which depends on the stereochemical features and conformational mobility of the central scaffold in the molecules examined. This agrees with the idea that dipolar charged, spatially close, aromatic moieties are important topochemical elements in the mechanism of action of these receptor antagonists. Molecular mechanics calculations allowed us to build up hypothetical, low-energy conformations of a few representative pseudopeptides, whose structural features are consistent with the experimental findings.
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Péptidos/química , Péptidos/farmacología , Dicroismo Circular , Modelos Moleculares , Espectrometría de FluorescenciaRESUMEN
Short linear peptides, carrying an AA spacer in the backbone chain (AA = Aib or Ala), and naphthalene (N) and protoporphyrin IX (P) covalently bound to epsilon-amino groups of lysine side chains, were synthesized. The general formula is Boc-Leu-Leu-Lys(P)-(AA)n-Leu-Leu-Lys(N)-OtBu, with n = 0-2. The photophysical behavior of these compounds was investigated in water/methanol 75/25 (v/v) solution by steady-state and time-resolved fluorescence experiments. Quenching of excited naphthyl chromophore takes place by electronic energy transfer to the porphyrin ground state, and proceeds on a time scale of 3-8 ns, while a minor and slower (approximately 45 ns) fluorescence lifetime measures the decay of the exciplexes. The results were compared with those earlier obtained with the P(Ala)nN peptides (n = 0-4) in methanol solution, showing that addition of water does not significantly alter the dynamic relaxation behavior of the systems investigated, but affects the dissipation mechanism of the energy transferred to P. Quenching efficiencies from both fluorescence intensity and fluorescence lifetime measurements follow a different trend as the number of AA units increases, depending on whether AA = Aib or Ala, indicating that there are differences in the structural features of the two series of peptides. Consistently, CD spectral results suggest that the former compounds attain ordered conformations, possibly of the 3(10)-helical type, while the latter populate alpha-helical structures to an extent depending on the chain length. The ir data in dilute CD3OD or CDCl3 solution confirm this conclusion in that there is an increased percentage of intramolecular H bonds in the P(Aib)nN as compared to the corresponding P(Ala)nN peptides. The photophysical results can be well described by a long-range dipole-dipole interaction model, provided the separation distances distribution and mutual orientation of N and P groups are taken into account. The need of using the angular relationships between the probes implies that interconversion among conformational substates of chromophores linkages is slow on the time scale of the transfer process, very likely because of both the amide bond in the linkages and the bulkiness of the donor-acceptor pair.
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Naftalenos , Oligopéptidos/química , Conformación Proteica , Protoporfirinas , Secuencia de Aminoácidos , Dicroismo Circular , Transferencia de Energía , Indicadores y Reactivos , Datos de Secuencia Molecular , Oligopéptidos/síntesis química , Espectrofotometría Infrarroja , Relación Estructura-ActividadRESUMEN
A spectroscopic investigation, based on both electronic absorption and emission spectra as well as on chiroptical data, was performed on novel neurokinin 1 (NK1) tachykinin receptor antagonists, exhibiting interesting biological activity. These pseudopeptides have two fluorophores, i.e. indole (I) and naphthalene (N), and a central scaffold with different conformational mobility. Absorption spectra in methanol show the presence of a new band with respect to the sum spectrum of the isolated chromophores at around 285 nm, the intensity of which linearly increases as the bioactivity increases. This absorption disappears by using dioxane as solvent. It is ascribed to an intramolecular I-N charge-transfer (CT) complex that forms to different extent, depending on the flexibility of the scaffold. Under this condition, the molecules fold and apparently attain the correct conformation for competing substance P binding to the NK1 receptor, lending plausibility to the role of dipolar charged, spatially close aromatic moieties as topochemical elements in the mechanism of action of substance P antagonists. The excited-behavior parallels that in the ground state, as the quenching of the singlet state at 340 nm is found to be linearly dependent on the biological activity, too. Upon decreasing solvent polarity (methanol vs dioxane) the emissions of the dipolar state at around 370 nm disappears, while exciplex emission in the range of 400-500 nm occurs. This transition from charge-separated to exciplex-like states by lowering the dielectric constant of the medium very likely reflects a change in the structural features of the intramolecular I-N stacked complex, from a twisted or an asymmetrically overlapped conformation of the indolyl and naphthyl rings to a face-to-face geometry. Implications of the rigidity of the molecules, arising from the formation of the intramolecular CT complex, on the ellipticity are briefly discussed.