The interactions of 16‐ferrocenylidene‐3α‐hydroxy androstan‐17‐one (
Synthesis and structural studies of 16‐ferrocenemethyl‐estra‐1,3,5(10)‐triene‐3,17β‐diol and its interaction with human serum albumin by fluorescence spectroscopy and in silico docking approaches
16‐Ferrocenylmethyl‐estra‐1,3,5(10)‐triene‐3,17β‐diol crystallizes in a triclinic unit cell and P1 space group. It contains four crystallographic independent molecules in the unit, representing four different conformers of the ferrocene–hormone conjugate. It provides evidence of a low rotational barrier around C19–C20and the existence of alpha and beta conformers. The four conformers are interconnected by hydrogen bonds through hydroxyl groups of rings A and D. Density functional theory studies show the rotational barrier energy to be 4.96 Kcal/mol and the preferred conformer has a dihedral angle φ2 (defined as C16–C19–C20–C21) of 85.79°. This angle represents the conformer with the lowest steric strains. Docking studies between the subject compound and human serum albumin (HSA) showed that the most likely binding pocket of HSA is drug‐binding site 2. Quenching fluorescence spectroscopy was used to study HSA–ferrocene conjugate interaction and results showed that the complex formation was static and dominated by van der Waals and electrostatic/hydrogen bonding interactions.
more » « less- NSF-PAR ID:
- 10457876
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Applied Organometallic Chemistry
- Volume:
- 34
- Issue:
- 4
- ISSN:
- 0268-2605
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract 1 ), 16‐ferrocenylidene‐3β‐hydroxy androstan‐17‐one (2 ), 21‐ferrocenylidene‐3β‐hydroxy pregn‐5‐en‐20‐one (3 ), and 16‐ferrocenylidene‐3β‐hydroxydehydro androstan‐17‐one (4 ) with human serum albumin (HSA) have been studied by fluorescence quenching spectroscopy and in silico docking calculations. The experimental results showed that the intrinsic fluorescence of HSA is quenched upon addition of the ferrocene‐steroid conjugates and the quenching mechanism is static. Thermodynamic parameters demonstrated that the protein‐ferrocene interactions are spontaneous, highly entropic, and hydrophobic. Protein‐ligand docking studies were performed using AutoDock Vina Program. Docking studies corroborated the experimental data, and the binding interactions are hydrophobic. All ferrocene‐steroid conjugates get engaged in hydrophobic interactions with LEU387, TYR411, LEU430, and ARG485 amino acid residues. -
null (Ed.)Tolnaftate, a classic antifungal compound, has been found to crystallize from 1:1 ( v / v ) acetone–water as large flat colorless needles in the centrosymmetric monoclinic space group P 2 1 / c . These crystals contain a 50:50 mixture of the (+ ap ,− sp ,+ ac ,− ac ) and (− ap ,+ sp ,− ac ,+ ac ) conformers. The bond lengths in the central CNOS unit are 1.3444 (19), 1.3556 (18) and 1.6567 (15) Å for C—N, C—O and C—S, respectively, and the CNOS and C 3 N moieties are flat and nearly coplanar with each other, consistent with the C—N bond possessing partial double-bond character. Tolnaftate and the four most closely related N , N -disubstituted thiocarbamates in the Cambridge Structural Database (CSD) all exist as E -conformational isomers in the solid state. Among these five compounds, tolnaftate is the only one in which the N -tolyl moiety is positioned trans to the S atom, i.e. the N -aryl substituent in each of the other compounds is positioned cis to their respective S atom. Notably, and more importantly, our experimental X-ray structure is unlike all prior theoretical models available for tolnaftate. The implication, either directly or indirectly, is that some of those theoretical models used in earlier studies to explain the spectroscopic properties of tolnaftate and to suggest which protein–ligand interactions are responsible for the binding of tolnaftate to squalene epoxidase are either inappropriate or structurally unreasonable, i.e. the results and conclusions from those prior studies are in need of critical reassessment.more » « less
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Harmata, Michael (Ed.)Several years ago, a small family of diterpenoid natural products attracted our attention as novel targets for synthesis studies. Initially, four compounds were independently characterized by the research teams of Vidari1 and Steglich.2 Trichoaurantianolides AeD (1e4 of Fig. 9.1) were isolated from fruiting bodies of the mushrooms Tricholoma aurantium and Tricholoma fracticum in 1995. Subsequent efforts of Stermer and coworkers3 described the isolation of the closely related lepistal (5) and lepistol (6) of Fig. 9.2 as the corresponding C8 deoxygenated compounds of this family. In addition, the corresponding acetate of trichoaurantianolide B was discovered and named as 6-O-aetyl- trichoaurantin (7).2 Structure assignments were based upon extensive nuclear magnetic resonance (NMR) studies, and the features of relative stereo- chemistry were confirmed by an X-ray crystallographic analysis of trichoaurantianolide B (2).1b,2 These original investigators described the trichoaurantianolides as examples of a new class of diterpenes named as neodolastanes that signified a structural relationship to the tricyclic metabo- lites of marine origins known as dolastanes as represented by dolatriol (8)4 and the clavularane 95 of Fig. 9.2. Neodolastanes were defined as substances in which the bridgehead methyl substituent appears in a vicinal relationship with respect to the isopropyl group as exemplified in 4,5-deoxyneodolabelline (10) of Fig. 9.2, a related class of marine natural products.6 Steglich and coworkers2 also indicated an assignment of absolute stereo- chemistry for 2 that was based on Hamilton’s applications of linear-hypothesis testing of crystallographic data. This seldom-used technique was in agreement with the proposed absolute configuration of 2 that was advanced by Vidari, based on an assessment of the observed Cotton effects in CD spectroscopy. In 2003, Ohta and coworkers7 reported the discovery of related neodolastanes tricholomalides A, B, and C (structures 11, 12, and 13 of Fig. 9.3) from Tricholoma sp. They concluded that the tricholomalides possessed the opposite absolute configuration claimed for the trichoaurantianolides. This conclusion was based upon the independent analysis of their circular dichroism studies. By application of the octant rule for substituent effects on cisoid a,b- unsaturated ketones,8 Ohta and coworkers suggested a revision of the prior assignment of absolute configuration for the trichoaurantianolides. This asser- tion was advanced in spite of the consistently positive specific rotations recorded in different solvents for trichoaurantianolides A, B, and C1,2 versus the negative values of tricholomalides A (11) and B (12) (compare values in Figs. 9.1 and 9.3). Note that tricholomalide C (13) only differs from trichoaurantianolide B (2) as a C-8 diastereomeric alcohol, presented in the antipodal series. The specific rotation of 13 was of little value since it was recorded as [a]0 (c 0.01, MeOH).7 In 2006, Danishefsky described a pathway for the total synthesis of racemic tricholomalides A and B, and this effort led to a revision of the relative C-2 stereochemistry (Fig. 9.3; revised structures 14 and 15).9 It seemed rather unusual that genetically similar fungi would produce closely related metabolites as enantiomers, but certainly this is not unprecedented. As a starting point, this issue lacked clarity, and we concluded that our synthesis plans must unambig- uously address the issues of absolute configuration. The chemistry of dolabellane and dolastane diterpenes has been reviewed.10 The proposed pathway for biosynthesis of the trichoaurantianolides and related compounds (Fig. 9.4) follows an established sequence from geranyl- geranyl pyrophosphate (16), which undergoes p-cation cyclization to initially form the eleven-membered ring of 17. The event is followed by a second cyclization to form the dolabellane cation 18, and this [9.3.0]cyclotetradecane skeleton is central to several families of natural products. Direct capture or elimination from 18 leads to the 3,7-dolabelladiene 19, which presents the most common pattern of unsaturation within this class. Compounds within this group are traditionally numbered beginning with C-1 as the bridgehead carbon bearing the methyl group rather than following the connectivity presented in ger- anylgeranyl 16. The cation 18 also undergoes a 1,2-hydrogen migration and elimination, which leads to a transannular cyclization yielding the 5e7e6 tri- cyclic dolastane 20. The secodolastanes, represented by 21, are a small collec- tion of marine natural products, which arise from oxidative cleavage of C10eC14 in the parent tricycle 20. In analogous fashion, the neodolabellane structure 22 is produced from 18 by stereospecific backbone migrations that result in the vicinal placement of the bridgehead methyl and isopropyl substituents. Transannular cyclizations, stemming from 22, yield the class of neodolastane diterpenes (23). Trichoaurantianolides and the related lepistal A (5) are the result of oxidations and cleavage of the C-ring (C4eC5) of 23, which leads to the features of an unusual butyrolactone system. The guanacastepenes, such as 24,11 and heptemerones, such as 25,12 are primary examples of the 5e7e6 neodolastane family, and these metabolites have also been isolated from fungi sources. A characteristic structural feature is the vicinal, syn-relationship of the bridgehead methyl and isopropyl sub- stituents as compared with the 1,3-trans relationship found in dolastanes (Fig. 9.2, structures 8 and 9). Guanacastepenes have proven to be attractive targets for synthesis studies.11,13 However, these fungal metabolites exhibit the antipodal, absolute stereochemistry as compared with neodolastanes from marine origins, such as sphaerostanol (26) (Fig. 9.5).14more » « less
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High-resolution direct absorption infrared spectra of metastable cis-formic acid (HCOOH) trapped in a cis-well resonance behind a 15 kcal/mol barrier are reported for the first time, with the energetically unstable conformer produced in a supersonic slit plasma expansion of trans-formic acid/H 2 mixtures. We present a detailed high-resolution rovibrational analysis for cis-formic acid species in the OH stretch ( ν 1 ) fundamental, providing first precision vibrational band origin, rotational constants, and term values, which in conjunction with ab initio calculations at the couple-cluster with single, double, and perturbative triple [CCSD(T)]/ANOn (n = 0, 1, 2) level support the experimental assignments and establish critical points on the potential energy surface for internal rotor trans-to-cis isomerization. Relative intensities for a- and b-type transitions observed in the spectra permit the transition dipole moment components to be determined in the body fixed frame and prove to be in good agreement with ab initio CCSD(T) theoretical estimates but in poor agreement with simple bond-dipole predictions. The observed signal dependence on H 2 in the discharge suggests the presence of a novel H atom radical chemical mechanism for strongly endothermic “up-hill” internal rotor isomerization between trans- and cis-formic acid conformers.more » « less
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Bis(bithienyl)-1,2-dicyanoethene (4TCE) is a photoswitch that operates via reversible E / Z photoisomerization following absorption of visible light. cis -to- trans photoisomerization of 4TCE requires excitation below 470 nm, is relatively inefficient (quantum yield < 5%) and occurs via the lowest-lying triplet. We present excitation-wavelength dependent (565–420 nm) transient absorption (TA) studies to probe the photophysics of cis -to- trans isomerization to identify sources of switching inefficiency. TA data reveals contributions from more than one switch conformer and relaxation cascades between multiple states. Fast (∼4 ps) and slow (∼40 ps) components of spectral dynamics observed at low excitation energies (>470 nm) are readily attributed to deactivation of two conformers; this assignment is supported by computed thermal populations and absorption strengths of two molecular geometries (P A and P B ) characterized by roughly parallel dipoles for the thiophenes on opposite sides of the ethene bond. Only the P B conformer is found to contribute to triplet population and the switching of cis -4TCE: high-energy excitation (<470 nm) of P B involves direct excitation to S 2 , relaxation from which prepares an ISC-active S 1 geometry (ISC QY 0.4–0.67, k ISC ∼ 1.6–2.6 × 10 −9 s −1 ) that is the gateway to triplet population and isomerization. We ascribe low cis -to- trans isomerization yield to excitation of the nonreactive P A conformer (75–85% loss) as well as loses along the P B S 2 → S 1 → T 1 cascade (10–20% loss). In contrast, electrocyclization is inhibited by the electronic character of the excited states, as well as a non-existent thermal population of a reactive “antiparallel” ring conformation.more » « less
