Benzoyl Ring Research Articles

Water‐Soluble Nitric‐Oxide‐Releasing Acetylsalicylic Acid (ASA) Prodrugs

A series of water-soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)-releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evaluated as ASA prodrugs. After conversion to the appropriate salt, most of the derivatives are solid at room temperature and all possess good water solubility. They are quite stable in acid solution (pH 1) and less stable at physiological pH. In human serum, these compounds are immediately metabolized by esterases, producing a mixture of ASA, salicylic acid (SA), and of the related NO-donor benzoic acids, along with other minor products. Due to ASA release, the prodrugs are capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma. Simple NO-donor benzoic acids 3-hydroxy-4-(3-nitrooxypropoxy)benzoic acid (28) and 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoic acid (48) were also studied as representative models of the whole class of benzoic acids formed following metabolism of the prodrugs in serum. These simplified derivatives did not trigger antiaggregatory activity when tested at 300 μM. Only 28 displays quite potent NO-dependent vasodilatatory action. Further in vivo evaluation of two selected prodrugs, {[2-(acetyloxy)benzoyl]oxy}methyl-3-[(3-[aminopropanoyl)oxy]-4-[3-(nitrooxy)propoxy]benzoate⋅HCl (38) and {[2-(acetyloxy)benzoyl]oxy}methyl 3-(morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoate oxalate (49), revealed that their anti-inflammatory activities are similar to that of ASA when tested in the carrageenan-induced paw edema assay in rats. The gastrotoxicity of the two prodrugs was also determined to be lower than that of ASA in a lesion model in rats. Taken together, these results indicated that these NO-donor ASA prodrugs warrant further investigation for clinical application.

2-Benzoyl-4-chlorophenyl benzoate

In the title compound, C20H13ClO3, the dihedral angles between the benzoate and the chloro­benzene and benzoyl rings are 68.82 (5) and 53.76 (6)°, respectively, while the dihedral angle between the benzoyl and benzoate rings is 81.17 (5)°. The eight atoms of the benzoyl residue are essentially planar with the exception of the O atom which lies 0.1860 (5) Å out of their mean plane (r.m.s. deviation = 0.97 Å). The nine atoms of benzoate residue are also essentially planar (r.m.s. deviation = 0.20 Å) with the ester O atom showing the greatest deviation [0.407 (12) Å] from their mean plane. In the crystal, mol­ecules are connected into centrosymmetric dimers by pairs of C—H⋯O hydrogen bonds.

Abstract 5493: Tumor-targeting with novel non-benzoyl 6-substituted pyrrolo[2,3-d]pyrimidine antifolates via cellular uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis.

Abstract Interest has focused on folate receptor (FR) α for delivering cytotoxic folate-based therapeutics to solid tumors, as FRα is highly expressed in certain tumors, including ovarian and non-small cell lung cancers. While FRα is present in normal epithelial tissues, this is restricted to apical membranes and is inaccessible to the circulation. Selectivity of FR-targeted agents would be further enhanced if these were poor substrates for the ubiquitously expressed reduced folate carrier (RFC). Both 5- and 6-substituted pyrrolo[2,3-d]pyrimidine benzoyl antifolates with 3 (AG19, AG126, respectively) and 4 (AG23, AG127, respectively) carbon bridge lengths potently inhibited proliferation of KB human tumor cells via uptake by FRα and inhibition of de novo purine nucleotide biosynthesis at β-glycinamide ribonucleotide formyltransferase (GARFTase) (all drugs) and 5-amino-4-imidazolecarboxamide ribonucleotide formyltransferase (AG126, AG127). Thienoyl-for-benzoyl B ring replacement in AG19 and AG23 increased inhibitory potencies, reflecting FRα uptake and increased GARFTase inhibition. To further examine the role in biological activities of the side chain benzoyl ring and terminal glutamate for this series, non-benzoyl 6-substituted pyrrolo[2,3-d]pyrimidine analogs were synthesized without a phenyl ring but with 5-8 carbon substituents with (AG143, AG145, AG147, AG149, respectively) and without a terminal glutamate. 5-Substituted analogs of AG145, AG147, and AG149 were also synthesized. Compounds were tested in proliferation assays with isogenic Chinese hamster ovary (CHO) sublines expressing RFC (PC43-10) or FRα (RT16). Additional testing was performed with KB human tumor cells. Analogs without a terminal glutamate and 5-substituted non-benzoyl pyrrolopyrimidine analogs were all inactive. AG143, AG145, AG147, and AG149 were also inactive with RFC- expressing CHO cells. For FRα-expressing RT16 and KB cells, growth inhibition was detectable in the order: AG147 ∼ AG149 > AG145 >> AG143. For AG147 and AG149, IC50s toward KB cells were ∼1 nM. Drug effects were abolished with excess folic acid, confirming FR uptake. Inhibition of cell proliferation was reflected in binding affinities to FRα, measured by competition with [3H]folic acid. By protection experiments with excess thymidine or adenosine, de novo purine nucleotide biosynthesis was confirmed as the targeted pathway for the active analogs. 5-Amino-4-imidazolecarboxamide also reversed the growth inhibitory effects of this series, establishing GARFTase as the principal intracellular target. Collectively, our studies establish an important structure-activity relationship for FRα-targeted antifolates, namely that a side chain benzoyl group is not essential for tumor selective drug uptake by FRα and for inhibition of GARFTase. Citation Format: Christina Cherian, Yiqiang Wang, Shermaine Mitchell-Ryan, Steven Orr, Zhanjun Hou, Aleem Gangjee, Larry H. Matherly. Tumor-targeting with novel non-benzoyl 6-substituted pyrrolo[2,3-d]pyrimidine antifolates via cellular uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5493. doi:10.1158/1538-7445.AM2013-5493

N-(4-Methylphenyl)-N-{[(2-nitrophenyl)acetyl]oxy}benzamide

In the title mol­ecule, C22H18N2O5, the nitro-substituted benzene ring makes dihedral angles of 71.56 (1)° with the benzoyl ring and 16.28 (1)° with the methyl-substituted benzene ring. The crystal structure features C—H⋯O inter­actions, which generate chains.

N-(2-Chlorophenyl)-1-phenylformamido 3-(2-nitrophenyl)propanoate

In the title mol­ecule, C22H17ClN2O5, the nitro-substituted benzene ring makes a dihedral angle of 79.22 (1)° with the benzoyl ring and 53.03 (1)° with the chloro-substituted benzene ring. An intra­molecular C—H⋯O hydrogen bond occurs. The crystal structure features weak C—H⋯Cl and C—H⋯O inter­actions.

N-(3-Nitrobenzoyl)benzenesulfonamide

In the title compound, C13H10N2O5S, the C=O bond in the —SO2—NH—CO— segment is anti to the meta-nitro group in the benzoyl ring, while the N—C bond has gauche torsions with respect to the S=O bonds. The molecule is twisted at the N atom with a dihedral angle of 79.9 (2)° between the sulfonyl benzene ring and the —SO2—NH—CO— segment. Furthermore, the dihedral angle between the benzeneline rings is 86.9 (2)°. In the structure, the mol­ecules are linked into helical chains along the b axis via N—H⋯O hydrogen bonds.

Weak Interactions between Folate and Osmolytes in Solution

Previous osmotic stress studies on the role of solvent in two structurally unrelated dihydrofolate reductases (DHFRs) found weaker binding of dihydrofolate (DHF) to either enzyme in the presence of osmolytes. To explain these unusual results, weak interactions between DHF and osmolytes were proposed, with a competition between osmolyte and DHFR for DHF. High osmolyte concentrations will inhibit binding of the cognate pair. To evaluate this hypothesis, we devised a small molecule approach. Dimerization of folate, monitored by nuclear magnetic resonance, was weakened 2-3-fold upon addition of betaine or dimethyl sulfoxide (DMSO), supporting preferential interaction of either osmolyte with the monomer (as it possesses a larger surface area). Nuclear Overhauser effect (NOE) spectroscopy experiments found a positive NOE for the interaction of the C3'/C5' benzoyl ring protons with the C9 proton in buffer; however, a negative NOE was observed upon addition of betaine or DMSO. This change indicated a decreased tumbling rate, consistent with osmolyte interaction. Osmotic stress experiments also showed that betaine, DMSO, and sucrose preferentially interact with folate. Further, studies with the folate fragments, p-aminobenzoic acid and pterin 6-carboxylate, revealed interactions for both model compounds with betaine and sucrose. In contrast, DMSO was strongly excluded from the pterin ring but preferentially interacted with the p-aminobenzoyl moiety. These interactions are likely to be important in vivo because of the crowded conditions of the cell where weak contacts can more readily compete with specific binding interactions.

4-Methoxybenzoyl-meso-octamethylcalix[2]pyrrolidino[2]pyrrole: an acyl chloride derivative of a partially reduced calix[4]pyrrole

In the title compound, C36H50N4O2, the two pyrrolidine rings have envelope conformations. The conformation of the macrocycle is stabilized by N—H⋯N hydrogen bonds and a C—H⋯N inter­action. The benzoyl ring is inclined to an adjacent pyrrole ring by 6.76 (9)°, with a centroid-to-centroid distance of 3.6285 (10) Å. In the crystal, apart from a C—H⋯O and a C—H⋯π inter­action, mol­ecules are linked via an N—H⋯O hydrogen bond, leading to the formation of helical chains propagating along [010].

4-Chlorobenzoyl-meso-octamethylcalix[2]pyrrolidino[2]pyrrole: an acyl chloride derivative of a partially reduced calix[4] pyrrole

In the title compound, C35H47ClN4O, the two pyrrolidine rings have envelope conformations. The conformation of the macrocycle is stabilized by N—H⋯N hydrogen bonds and a C—H⋯N inter­action. The benzoyl ring is inclined to the adjacent pyrrole ring by 11.66 (11)°, with a centroid–centroid distance of 3.7488 (13) Å. In the crystal, molecules are linked by N—H⋯O hydrogen bonds into helical chains propagating in [010] and C—H⋯O and C—H⋯π interactions are also observed.

EthylN-(2-benzoyl-4-chlorophenyl)ethanecarboximidate

In the title compound, C17H16ClNO2, the N=C—O—C—C fragment is planar within 0.029 (1) Å, and makes dihedral angles of 66.71 (8) and 59.61 (8)° with the planes of the chloro­phenyl and benzoyl rings, respectively. The carbonyl C=O bond is not coplanar with either of the aromatic rings; it makes angles of 42.5 and 23.5° with the normals to the ring planes. In the crystal, very weak C—H⋯O, C—H⋯Cl, C—H⋯π and π–π [inter­planar distance = 3.53 (1) Å] inter­actions are observed.

4-Chloro-N-(3,5-dimethylphenyl)benzamide

In the mol­ecular structure of the title compound, C15H14ClNO, the amide group forms dihedral angles of 15.8 (2) and 27.2 (2)°, respectively, with the benzoyl and aniline rings, while the angle between the benzoyl and aniline rings is 11.5 (1)°. The crystal structure is stabilized by N—H⋯O hydrogen bonds, which give rise to infinite chains running along the c axis.

2-Chloro-N-(3-methylphenyl)benzamide

In the structure of the title compound, C14H12ClNO, the ortho-Cl atom in the benzoyl ring is positioned syn to the C=O bond, while the meta-methyl group in the aniline ring is positioned anti to the N—H bond. The amide group forms dihedral angles of 60.1 (1) and 22.0 (1)°, respectively, with the benzoyl and aniline rings, while the angle between these rings is 38.7 (1)°. The crystal structure is stabilized by N—H⋯O hydrogen bonds, which give rise to infinite chains running along the c axis.

N-(3-Chlorobenzoyl)-2-nitrobenzenesulfonamide

In the title compound, C13H9ClN2O5S, the N—C bond in the C—SO2—NH—C segment has a gauche torsion with respect to the S=O bonds. The conformation between the N—H bond and the ortho-nitro group in the sulfonyl benzene ring is syn, and that between the C=O and the meta-Cl atom in the benzoyl ring is anti. The mol­ecule is twisted at the S—N bond, with a torsion angle of 65.41 (38)°. The dihedral angle between the sulfonyl benzene ring and the –SO2—NH—C—O segment is 75.0 (1)°, and that between the sulfonyl and the benzoyl benzene ring is 89.1 (1)°. The crystal structure features inversion-related dimers linked by pairs of N—H⋯O(S) hydrogen bonds.

N-(3-Methylbenzoyl)-2-nitrobenzenesulfonamide

In the title compound, C14H12N2O5S, the conformation between the N—H group and the ortho-nitro group in the sulfonyl benzene ring is syn and that between the C=O and meta-methyl groups in the benzoyl ring is anti. The mol­ecule is twisted at the S—N bond with a torsion angle of 64.3 (2)°. The dihedral angle between the sulfonyl benzene ring and the —SO2—NH—C—O segment is 75.73 (7)° and that between the sulfonyl and benzoyl benzene rings is 89.5 (1)°. The crystal structure features inversion-related dimers linked by pairs of N—H⋯O(S) hydrogen bonds.

Crystal Structure of (4-Benzoyl-2-methyl-phenoxy)-acetic acid ethyl ester

The structure of the title compound, (4-benzoyl-2-methyl-phenoxy)-acetic acid ethyl ester (C18H18O4), was established by spectral analysis and X-ray diffraction studies. The compound crystallizes in the orthorhombic space group Pbca with the following unit-cell parameters: a = 36.993(2), b = 10.1567(7), c = 8.3441(6)A, Z = 8. The crystal structure was solved by direct methods using single-crystal X-ray diffraction data collected and refined by full-matrix least-squares procedures to a final R-value of 0.0690 for 2155 observed reflections. The dihedral angle between the benzoyl ring and the methyl substituted phenyl ring is 59.4(1)°. The crystal structure is stabilized by C-H…O and C-H…π hydrogen bonds that link the molecules into infinite chains.

Update on twice-daily bromfenac sodium sesquihydrate to treat postoperative ocular inflammation following cataract extraction

Ophthalmic bromfenac sodium sesquihydrate is a topically applied selective cyclooxygenase (COX)-2 inhibitor. It is similar to amfenac, except for a bromine atom at the C4 of the benzoyl ring position, which markedly affects its in vitro and in vivo potency, extends the duration of anti-inflammatory activity, and enhances its inhibitory effect on COX-2 absorption across the cornea and penetration into ocular tissues. The United States Food and Drug Administration approved bromfenac in 2005 for the treatment of postoperative inflammation and the reduction of ocular pain in patients who have undergone cataract surgery. Nonsteroidal anti-inflammatory drugs (NSAIDs), and among them bromfenac, could be even more effective than steroids at reestablishing the blood–aqueous barrier, as revealed by flare on slit-lamp examination and as quantitatively measured using ocular fluorophotometry. Similar to other NSAIDs, it has a role in inhibiting intraoperative miosis during cataract surgery. However, bromfenac also seems to be useful in other situations, such as refractive surgery, allergic conjunctivitis (not useful in dry eye), choroidal neovascularization, and even ocular oncology. No reports of systemic toxicity have been published and bromfenac has good topical tolerance with a low incidence of adverse effects.

4-Chloro-N-(2,3-dimethylphenyl)benzamide

In the title compound, C15H14ClNO, the ortho- and meta-methyl substituents in the aniline ring are anti to the N—H bond. The dihedral angle between the benzoyl and aniline benzene rings is 95.0 (1)°. N—H⋯O hydrogen bonds and C—H⋯π inter­actions link the mol­ecules in the crystal structure.

3-Chloro-N-(2-chlorophenyl)benzamide

In the title compound, C13H9Cl2NO, the meta-Cl atom in the benzoyl ring is positioned anti to the C=O bond, while the ortho-Cl atom in the aniline ring is positioned syn to the N—H bond. The two aromatic rings are almost coplanar, making a dihedral angle of 4.73 (5)°. The crystal structure is stabilized by N—H⋯O hydrogen bonds, which link the mol­ecules into chains along the b axis.

N-(3-Chlorobenzoyl)-2-methylbenzenesulfonamide

In the title compound, C14H12ClNO3S, the N—H bond in the C—SO2—NH—C(O) segment is anti to the C=O bond. Further, the C=O bond and the meta-Cl atom in the benzoyl ring are also anti to each other. The dihedral angle between the sulfonyl and the benzoyl benzene rings is 72.4 (1)°. In the crystal, mol­ecules are linked by pairs of N—H⋯O hydrogen bonds, forming inversion dimers.

1-Benzoyl-4-(4-methylphenyl)phthalazine

In the title mol­ecule, C22H16N2O, the tolyl and benzoyl rings make dihedral angles 50.2 (5) and 56.4 (5)°, respectively, with the phthalazine ring system while the dihedral angle between the tolyl and benzoyl rings is 0.70 (4)°. The crystal structure is stabilized by inter­molecular C—H⋯O and C—H⋯N hydrogen bonds, as well as weak C—H⋯π inter­actions.