Comment on "Asymmetric Bistricyclic Aromatic Enes".

This Correspondence argues against the use of the adjectives "symmetrical" and "asymmetric" in the recent publication entitled "Fluorenylidene-Cyclopentadithiophene Based Asymmetric Bistricyclic Aromatic Ene Compounds: Synthesis and Substituents Effects", by Beibei Xiao, Yongrui Yang, Shengnan Chen, Ye Zou, Xing Chen, Kanglei Liu, Nan Wang, Yali Qiao, and Xiaodong Yin (Chem. Eur. J., 2023, 29, e202301055).[1].

The Quest for Secondary Pharmaceuticals: Drug Repurposing/Chiral-Switches Combination Strategy.

Drug repurposing toward new medical uses and chiral switches are elements of secondary pharmaceuticals. The drug repurposing and chiral-switches strategies have mostly been applied independently in drug discovery. Drug repurposing has peaked in the search for therapeutic treatments of the Coronavirus Disease 2019 pandemic, whereas chiral switches have been overlooked. The current Perspective introduces the drug repurposing/chiral-switches combination strategy, overviewing representative cases of chiral drugs that have undergone this combination: ketamine, flurbiprofen, fenfluramine, and milnacipran. The deuterium-enabled chiral switches of racemic thalidomide analogs, a variation of the repurposing/chiral-switch combination strategy, is also included. Patenting and regulatory-exclusivity considerations of the combination strategy in the discovery of new medical uses are considered. The proposed combination creates a new synergy of its two elements, overcoming arguments against chiral switches, with better prospects for validation of patents and regulatory exclusivities. The combination strategy may be applied to chiral switches to paired enantiomers. Repurposing/chiral-switch drugs may be 'obvious-to-try'; however, their inventions may be unexpected and their patents nonobvious. Patenting repurposing/chiral-switch combination drugs is not 'evergreening', 'product hopping', and 'me-too'. The expected benefits and opportunities of the combined repurposing/chiral-switch strategy vis-à-vis its two elements are superior pharmacological properties, overcoming arguments against patent validities, challenges of chiral-switch patents, reduced expenses, shortened approval procedures, and higher expectations of regulatory exclusivities.

Distinction between 2'- and 3'-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration.

Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2'- and 3'-phosphate derivatives, a difference used to improve the specificity of inhibition by isolated 2'- and 3'-phosphate isomers of our NADPH analogue NS1. Both isomers become fluorescent upon binding to their target proteins as observed by in vitro assay and in vivo imaging. The 2'-phosphate isomer of NS1 exerted more pronounced effects on NOS and NOX-dependent physiological responses than the 3'-phosphate isomer did. Docking and molecular dynamics simulations explain this specificity at the level of the NADPH site of NOX and NOS, where conserved arginine residues distinguished between the 2'-phosphate over the 3'-phosphate group, in favor of the 2'-phosphate.

In Defense of Secondary Pharmaceutical Patents in Drug Discovery and Development.

"An important objective of modern pharmaceutical research is the discovery of new medical uses for known molecules" (UKSC 2018), a component of secondary pharmaceuticals. This Viewpoint's focus is the defense of the vulnerable strategy of secondary pharmaceutical patents (SPPs). Typical claims thereof are new medical uses, dosage, selection, and enatiomer patents. The attacks on secondary pharmaceuticals, including chiral switches, use negative-connotation terms, such as "evergreening", "product hopping", and "pejorative". Most enantiomer patents, including the controversial Nexium patents, were challenged in courts worldwide yet validated. This Viewpoint considers the "teaching away" defense of nonobviousness of Nexium enantiomer patents due to "unexpected results", applying stereochemistry principles. Physical organic chemistry arguments and the prediction of lower energy barriers of epimerization/racemization of benzylic anions of esomeprazole and dexlansoprazole (compared with their uncharged enantiomers) are a basis of the "teaching away". This prediction is verified by DFT computations. "Obvious to try" of many SPPs should not prevail over "unexpected results". A generalized concern about "evergreening" drugs should not be a justification for comprehensive attacks on SPPs. Following UKSC Lyrica decision (2018), plausibility, a condition of patent validity, may enter the arena of enantiomer patents, claiming second medical uses. Secondary pharmaceutical dosage, selection, improvement, and enantiomer patents are not necessarily obvious.

Regioselectivity in the Controversial Scholl Reaction of 1-Benzoylpyrene: Formation of a Five-Member Ring Is Not Unexpected.

Intramolecular Scholl reaction of 1-benzoylpyrene (1) gave 8H-dibenzo[def,qr]chrysen-8-one (2) and 11H-indeno[2,1-a]pyren-11-one (3) in a 1:2 ratio. The structures of 2 and 3 were determined, using 1H NMR, 13C NMR, and IR spectroscopies. A DFT B3LYP/6-311G(d,p) study of the reaction's arenium-cation mechanism of (E)-1 and (Z)-1 giving 2 and 3, respectively, indicated the reaction's regioselectivity and kinetic control. The analogous reaction of 1-(1'-naphthoyl)pyrene gave exclusively 13H-benz[4,5]indeno[2,1-a]pyren-13-one. Contrary to previous claims, the preferred formation of five-member rings in Scholl reactions is not unexpected.

Classroom Enters the Courtroom: Stereochemistry of SN1 and SN2 Reactions in Enantiomer Patent Litigations of the Antidepressant Escitalopram.

The role of elementary stereochemistry is illustrated in the patent litigations of the blockbuster antidepressant drug escitalopram oxalate. An undergraduate student of organic chemistry would recognize the stereochemical courses of the intramolecular SN 2 and SN 1 reactions of the single-enantiomer (S)-diol intermediate in the synthesis of the blockbuster antidepressant drug escitalopram oxalate: retention of configuration of the chiral carbon atom under basic conditions and racemization under acidic conditions, respectively. He/she, in searching for a stereoselective ring-closure reaction of the enantiomeric diol, will think of an SN 2 reaction in a basic medium. From these points of view, the process claim in the enantiomer patents of escitalopram is obvious/lacks an inventive step. An organic chemistry examination problem based on this scenario is offered.

Heteromerous Bistricyclic Aromatic Enes: Dynamic Stereochemistry of Xanthylidene-Anthrones.

The heteromerous bistricyclic aromatic ene (BAE) 2,2'-dimethyl-10-(9H-xanthylidene)-9(10H)-anthrone (DMXA) was synthesized by a condensation of 10,10-dichloro-2-methylxanthene with 2-methylanthrone. X-ray crystallography of (E)-DMXA and xanthylidene-anthrone (XA) indicated that the molecules adopt anti-folded conformations with folding dihedral angles of 44°/44° and 39°/41°, respectively. The crystal structure of anti-folded (E)-DMXA does not indicate any xanthenylium-anthracenolate push-pull effect. E,Z-diastereomerization of DMXA was studied by (1) H-NMR coalescence-temperature measurements at different magnetic field strengths and by kinetic equilibration experiments. Free energy of activation for this process was 81.5 (±1.3) kJ/mol. B3LYP/6-311+G(d,p) calculations showed that anti-folded conformers of XA, (E)-DMXA, bianthrone (AA), and dixanthylene (XX) were global minima. The twisted conformers of XA, AA, and XX were local minima (ΔG298 = 16, 18, and 24 kJ/mol) with a substantial dipolar xanthenylium-anthracenolate dipolar contribution for XA. Chirality 27:919-928, 2015. © 2015 Wiley Periodicals, Inc.

"New drug" designations for new therapeutic entities: new active substance, new chemical entity, new biological entity, new molecular entity.

This Perspective addresses ambiguities in designations of "new drugs" intended as new therapeutic entities (NTEs). Designation of an NTE as a new drug is significant, as it may confer regulatory exclusivity, an important incentive for development of novel compounds. Such designations differ between jurisdictions according to their drug laws and drug regulations. Chemical, biological, and innovative drugs are addressed in turn. The terms new chemical entity (NCE), new molecular entity (NME), new active substance (NAS), and new biological entity (NBE) as applied in worldwide jurisdictions are clarified. Differences between them are explored through case studies showing why new drugs have different periods of exclusivity in different jurisdictions or none at all. Finally, this Perspective recommends that in future, for the purpose of new drug compilations, NME is used for a new chemical drug, NBE for a new biological drug, and the combined designation NTE should refer to either an NME or an NBE.

Stereochemistry of bistricyclic aromatic enes and related polycyclic systems.

Bistricyclic aromatic enes (BAEs) and related polycyclic systems are a class of molecular materials that display a rich variety of conformations, dynamic stereochemistry and switchable chirality, color, and spectroscopic properties. This is due to the a subtle interplay of the inherent preference for planarity of aromatic systems and the competing necessity of non-planarity due to intramolecular overcrowding in the fjord regions built into the general molecular structure of BAEs. The conformational, dynamic, and spectroscopic properties may be designed and fine-tuned, e.g., by variation of the bridging groups X and Y, the overcrowding in the fjord regions, extensions of the aromatic system, or other modifications of the general BAE structure, based on the fundamental understanding of the structure-property relationships (SPR). The present review provides an analysis of the conformational spaces and the dynamic stereochemistry of overcrowded bistricyclic aromatic enes applying fundamental symmetry considerations. The symmetry analysis presented here allows deeper insight into the conformations, chirality, and the mechanisms of the dynamic stereochemistry, and will be instrumental in future computational studies.

Single enantiomer versus racemate: chiral distinction in the proton pump inhibitors omeprazole and esomeprazole.

Chiral distinction in the proton pump inhibitor drugs omeprazole and in its chiral-switch esomeprazole magnesium was studied employing the Density Functional Theory (DFT) method. At B3LYP/6-311G(d,p), the 6-methoxy∙∙∙6-methoxy and 5-methoxy∙∙∙5-methoxy homochiral and heterochiral dimers were calculated. The chiral distinction free energies (ΔΔG(298,(RS-SS))) between the cyclic C2-(S,S)- and Ci-(R,S)-dimers with two intermolecular hydrogen bonds are 3.8, 1.9 (with BSSE counterpoise correction), and -6.9 (with D3 dispersion and BSSE counterpoise corrections) kJ/mol. Adding water as an implicit solvent (polarized continuum model [PCM] model) resulted in a chiral distinction energy of -3.3 kJ/mol, indicating a reversal of the order of the relative stabilities of C2-(S,S)- and Ci-(R,S)-dimers. The chiral distinction free energies between the corresponding (less stable) C1-dimers with one intermolecular hydrogen bond are -9.3, -5.8 (with BSSE CC), 17.6 (D3 + BSSE CC), and -3.2 (H2O) kJ/mol. The results highlight the contention that omeprazole is not just a superposition of its enantiomer constituents. They are consistent with the pharmacological evidence of enantiomer-enantiomer interactions in omeprazole versus esomeprazole and the differences between the drugs omeprazole and esomeprazole magnesium and support the lodged application for regulatory supplementary protection certificate (SPC) exclusivity for the esomeprazole-related combination drug Vimovo.

Racemization of the gastrointestinal antisecretory chiral drug esomeprazole magnesium via the pyramidal inversion mechanism: A theoretical study.

The pyramidal inversion mechanisms of the 6-methoxy and the 5-methoxy tautomers of (S)-omeprazole were studied, employing ab initio and DFT methods. The conformational space of the model molecule (S)-2-[(3-methyl-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole was calculated, with respect to rotations around single bonds, at the B3LYP/6-311G(d,p) level. All of the resulting conformations were used as starting points for full optimizations of (S)-omeprazole, at B3LYP/6-31G(d), B3LYP/6-311G(d,p), B3LYP/6-311++G(d,p), B3LYP/6-311G(2df,2pd), MP2/6-31G(d), and MP2/6-311G(d,p) levels. Four distinct pathways were found for enantiomerization via the pyramidal inversion mechanism for each of the tautomers of (S)-omeprazole. Each transition state, in which the sulfur, the oxygen and the two carbon atoms connected directly to the sulfur are in one plane, connects two diastereomeric minima. The enantiomerization is completed by free rotation around the sulfur-methylene bond, and around the methylene-pyridine ring bond. The effective Gibbs' free energy barrier for racemization DeltaG(double dagger) (rac) of the two tautomers of (S)-omeprazole are 39.8 kcal/mol (5-methoxy tautomer) and 40.0 kcal/mol (6-methoxy tautomer), indicating that the enantiomers of omeprazole are stable at room temperature (in the gas phase). The 5-methoxy tautomer of (S)-omeprazole was found to be slightly more stable than the 6-methoxy tautomer, in the gas phase. The energy barrier (DeltaG(++)) for the(S,M) <=>(S,P) diastereomerization of (S)-omeprazole due to the rotation around the pyridine chiral axis was very low, 5.8 kcal/mole at B3LYP/6-311G(d,p).

The strategy of enantiomer patents of drugs.

Enantiomer patents (ENPTs), constituents of chiral switches, claim single enantiomers of chiral drugs previously claimed as racemates. In this article, the strategy of ENPTs and recent court decisions and trends in case law worldwide are highlighted. ENPTs are challenged frequently (e.g. anticipation, obviousness, double patenting and insufficient disclosure), even though the novelty of enantiomers is not destroyed by the description of racemates. For establishing inventiveness (nonobviousness), the description in ENPTs should include superior pharmacological and/or pharmaceutical properties of enantiomer vis-á-vis racemate, above the expected 2:1 ratio. ENPTs were 'obvious-to-try' (unless taught away) since the mid-1980s. General concern about evergreening by ENPTs is not justified. ENPTs should be evaluated on a case-by-case basis. ENPT litigations are especially susceptible to settlements.

Electrostatic chiral distinction: tetrahedral model dimers.

Although chiral distinction plays a pervasive role in chemistry, a complete understanding of how this takes place is still lacking. In this work, we expand the earlier described minimal requirement of so called four-point interactions (vide infra). We focus on chiral point charge model systems as a means to aid in the dissection of the underlying, operative principles. We also construct models with defined symmetry characteristics. By considering extensive constellations of diastereomeric complexes, we are able to identify emerging principles for chiral distinction. As previously postulated, all the diastereomeric complexes, regardless of their nominal contact-points, possess a chiral distinction energy. In the comparison of complexes, we find that, contrary to chemical intuition, the magnitude of chiral distinction does not correlate with the stability of the complexes, i.e., consideration of low energy complexes may not be an effective way to evaluate chiral distinction. Similarly, we do not find a correlation between the number of contact-points and chiral distinction. Moreover, favorable interactions and facile chiral distinction appear to be unrelated. We also see some tendency for greater chiral distinction in less symmetric systems, although this may not be general. These studies can now form the basis to fold in higher levels of complexity into the models so as to gain further insights into the nature of chiral distinction.

Theoretical notions of aromaticity and antiaromaticity: phenalenyl ions versus fluorenyl ions.

The dications 6, 7, and 8 and dianions 9, 10, and 11 of the bistricyclic aromatic enes bifluorenylidene (1), 1,1'-biphenalenylidene (2), and 9-(9H-fluoren-9-ylidene)-1H-phenalene (4), as well as monocations 12a and 13a and monoanions 14a and 15a of phenalene (3) and fluorene (5), were subjected to a systematic DFT and ab initio study. B3LYP and MP2 methods were employed to estimate the relative aromaticity/antiaromaticity of these ions, using energetic, magnetic, and structural criteria. The couplings of monoions 12a-15a to give the respective diions 6-11 result in a similar destabilization in both the fluorene and phenalene series. The interactions between the C13H8 units in diions 6-11 are weak and are not expected to result in a significant loss of aromaticity/gain of antiaromaticity, as compared with the respective monoions. The antiaromaticity of bifluorenylidene dication (6), relative to that of two fluorenyl cations (12a), is only slightly enhanced as compared with the aromaticity of biphenalenylidene dication ((E)-7)) relative to that of two phenalenyl cations (13a). In particular, the homodesmotic reaction 6 + 2.13a = (E)-7 + 2.12a is only slightly exothermic, DeltaE(Tot) = -6.0 kJ/mol. The energetic effect of the analogous reaction involving anions 9 + 2.15a = (E)-10 + 2.14a is even smaller, DeltaE(Tot) = -3.4 kJ/mol. Bifluorenylidene dianion (9) and 1,1'-biphenalenylidene dianion ((E)-10) are aromatic, but the employed criteria disagree about their relative aromaticity. The electronic and structural properties of heteromerous dication 8 and dianion 11 lie between those of the homomerous diions. Thus, dications 6-8 and dianions 9-11 form a continuum of aromaticity/antiaromaticity.

Pyramidal inversion mechanism of simple chiral and achiral sulfoxides: a theoretical study.

The pyramidal inversion mechanism of simple sulfoxides was studied, employing ab initio and DFT methods. The convergence of the geometrical and energetic parameters of H2SO and DMSO with respect to the Hamiltonian and basis set was analyzed in order to determine a computational level suitable for methyl phenyl sulfoxide (3), methyl 4-cyanophenyl sulfoxide (4), diphenyl sulfoxide (5), 4,4'-dicyanodiphenyl sulfoxide (6), benzyl methyl sulfoxide (7) and benzyl phenyl sulfoxide (8). The DFT B3LYP/6-311G(d,p) level was chosen for further calculations of larger sulfoxides. The barriers DeltaE calculated for the pyramidal inversion mechanism of sulfoxides 3-8 are in the range of 38.7-47.1 kcal/mol. These values are in good agreement with the experimental barriers for racemization via the pyramidal inversion mechanism. A resonance effect of a phenyl ring selectively stabilizes the transition state conformations, decreasing the energy barrier for pyramidal inversion by about 3 kcal/mol, compared to a similar molecule without a phenyl substituent. Introducing electron withdrawing groups (cyano) at the para positions of the phenyl ring(s) causes a further decrease of the energy barrier.

Polymorphism versus thermochromism: interrelation of color and conformation in overcrowded bistricyclic aromatic enes.

The nature of the thermochromic form of overcrowded bistricyclic aromatic enes (BAEs) has been controversial for a century. We report the single-crystal X-ray structure analysis of the deep-purple and yellow polymorphs of 9-(2,7-dimethyl-9H-fluoren-9-ylidene)-9H-xanthene (11), which revealed the molecules in a twisted and a folded conformation, respectively. Therefore, the deeply colored thermochromic form B of BAEs is identified as having a twisted conformation and the ambient-temperature form A as having a folded conformation. This relationship between the color and the conformation is further supported by the X-ray structures of the deep-purple crystals of the twisted 9-(9H-fluoren-9-ylidene)-9H-xanthene (10), and of the yellow crystals of the folded 9-(11H-benzo[b]fluoren-11-ylidene)-9H-xanthene (12). Based on this conclusive crystallographic evidence, eleven previously proposed rationales of thermochromism in BAEs are refuted. In the twisted structures, the tricyclic moieties are nearly planar and the central double bond is elongated to 1.40 A and twisted by 42 degrees . In the folded structures, the xanthylidene moieties are folded by 45 degrees and the fluorenylidene moieties by 18-20 degrees . Factors stabilizing the twisted and folded conformations are discussed, including twisting of formal single or double bonds, intramolecular overcrowding, and the significance of a dipolar aromatic "xanthenylium-fluorenide" push-pull structure.

Conformational spaces of the gastrointestinal antisecretory chiral drug omeprazole: stereochemistry and tautomerism.

A study of the conformational spaces of the chiral proton pump inhibitor (PPI) drug omeprazole by semiempirical, ab-initio, and DFT methods is described. In addition to the chiral center at the sulfinyl sulfur atom, the chiral axis at the pyridine ring (due to the hindered rotation of the 4-methoxy substituents) was considered. The results were analyzed in terms of the 5-methoxy and 6-methoxy tautomers and the two pairs of enantiomers (R,P)/(S,M) and (R,M)/(S,P). Five torsion angles were systematically explored: the backbone rotations defined by D1 (N3-C2-S10-O11), D2 (C2-S10-C12-C13), and D3 (S10-C12-C13-N14) and two methoxy rotations defined by D4 (C6-C5-O8-C9) and D5 (C16-C17-O19-C20). Significant energy differences were revealed between the 5- and 6-methoxy tautomers, the extended and folded conformations, and the (S,M) and (S,P) diastereomers. The "extended M" conformation of the 6-methoxy tautomer of (S)-omeprazole was found to be the most stable conformer.

Two contact-point chiral distinction: model CHFClBr dimers.

Dimers of the simple chiral molecule CHFClBr have been studied using a variety of computational approaches, including HF, MP2, and DFT B3LYP and the 6-31G*, 6-31++G**, and 6-311++G** basis sets. Both heterochiral and homochiral dimers were studied to allow analysis of the chiral distinction in these systems. The dimers were arranged in edge-to-edge orientations with assorted combinations of two contact-points ("2:2e") between the dimers. The monomers were constrained to tetrahedral symmetry. We demonstrate that chiral distinction does indeed occur in these two contact-point models. While the stabilization energies are driven by the interactions of the nearest atoms (contacts) in the complexes, the degree of chiral distinction is driven by the profile of changing atoms, which, in the present systems, are often the distal atoms of the complexes. Moreover, the chiral distinction does not correlate with the stabilization energies. The terms contact-points and interactions are defined.