Semisynthesis and antibacterial activities of nidulin derivatives.

Derivatives of the fungal depsidone, nidulin, have been synthesized in order to evaluate the potential of the chemical skeleton as antibacterial agents. Alkylation, acylation, and arylation reactions of nornidulin underwent in a regioselective manner to predominantly produce 8-O-substituted derivatives. Many of the semisynthetic derivatives showed more potent antibacterial activities than nidulin, In particular, 8-O-aryl ether derivatives displayed significant activities against Gram-positive bacteria, including Methicillin-resistant Staphylococcus aureus.

Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer.

Poly (ADP-ribose) polymerase-1 (PARP1) is a highly conserved enzyme focused on the self-repair of cellular DNA damage. Until now, numbers of PARP inhibitors have been reported and used for breast cancer therapy in recent years, especially in TNBC. However, developing a new type PARP inhibitor with distinctive skeleton is alternatively promising strategy for TNBC therapy. In this study, based on co-crystallization studies and pharmacophore-docking-based virtual screening, we discovered a series of dihydrodibenzo[b,e]-oxepin compounds as PARP1 inhibitors. Lead optimization result in the identification of compound OL-1 (2-(11-(3-(dimethylamino)propylidene)-6,11- dihydrodibenzo[b,e]oxepin )-2-yl)acetohydrazide), which has a novel chemical scaffold and unique binding interaction with PARP1 protein. OL-1 demonstrated excellent potency (inhibiting PARP1 enzyme activity with IC50 = 0.079 µM), as well as inhibiting PARP-modulated PARylation and cell proliferation in MDA-MB-436 cells (BRAC1 mutation). In addition, OL-1 also inhibited cell migration that closely related to cancer metastasis and displayed remarkable anti-tumor efficacy in MDA-MB-436 xenograft model without apparent toxicities. These findings highlight a new small-molecule PAPR1 inhibitor (OL-1) that has the potential to impact future TNBC therapy.

FeCl3-catalyzed synthesis of functionally diverse dibenzo[b,f]oxepines and benzo[b]oxepines via alkyne-aldehyde metathesis.

An efficient synthesis of dibenzo[b,f]oxepines and benzo[b]oxepines via FeCl3-catalyzed alkyne-aldehyde metathesis reaction is described. Structurally diverse dibenzo[b,f]oxepines and benzo[b]oxepines have been achieved in good yields with high regio- and chemoselectivity under mild conditions. Notably, among the various catalysts such as Fe(III), Au(III), In(III), Zn(II), Ag(I) and triflic acid, the alkyne-aldehyde metathesis reaction of 2-(2'-phenylethynyl-phenyloxy)-benzaldehyde is only catalyzed by environmentally friendly and sustainable iron(III) chloride.

First total synthesis of dioxepine bastadin 3.

The synthesis of dioxepine bastadin 3, a tyrosine-tyramine derivative with a dibenzo-1,3-dioxepine scaffold that is rarely present among natural products, is described. The dibenzo-1,3-dioxepine ring was formed early in the sequence and the (E)-2-(hydroxyimino)-N-alkylamide was generated in the last step by oxidation of the 2-amino-N-alkylamide precursor. The presumably biogenetic late-stage ring formation starting from congener bastadin 3 failed. A new synthesis of this alkaloid was also developed. This new route requires a minimal use of protecting groups and the order of the two key steps was reversed relative to the route to dioxepine bastadin 3.

Stereoselective syntheses of the antihistaminic drug olopatadine and its E-isomer.

Practical stereoselective synthetic routes to the antihistaminic drug olopatadine and its E-isomer have been developed, the key steps being a trans stereoselective Wittig olefination using a nonstabilized phosphorus ylide and a stereoselective Heck cyclization. The stereoselectivity of the Wittig reaction depends on both the phosphonium salt anion and the cation present in the base used to generate the ylide.

Synthesis of tricyclic compounds as steroid 5alpha-reductase inhibitors.

A series of 4-phenoxybutyric acid derivatives attached to a tricyclic skeleton were prepared and evaluated as 5alpha-reductase inhibitors. Structure activity relationships for these compounds in terms of rat epididymis (type 2) 5alpha-reductase inhibitory activities reveal that 1) the substitution pattern at the 11-position of dibenz[b,e]oxepin influenced potency, 2) higher lipophilicity of the tricyclic skeleton improved potency, whereas the existence of a basic nitrogen atom in this skeleton was detrimental to potency, and 3) isobutyl substitution at the 8 positon of the azepine skeleton was tolerated. Among the tricyclic compounds studied, 4-[3-[5-benzyl-8-(2-methyl)propyl-10,11-dihydrodibenz[b,f]azepine- 2-carboxamido]phenoxy]butyric acid (26) was the most potent inhibitor of rat type 2 5alpha-reductase at 0.1 microM.

Dibenzoxepinone hydroxylamines and hydroxamic acids: dual inhibitors of cyclooxygenase and 5-lipoxygenase with potent topical antiinflammatory activity.

Hydroxylamine and hydroxamic acid derivatives of a known nonsteroidal antiinflammatory dibenzoxepine series display both cyclooxygenase (CO) and 5-lipoxygenase (5-LO) inhibitory properties. Many of these new dual CO/5-LO inhibitors also exhibit potent topical antiinflammatory activity in the arachidonic acid-induced murine ear edema model. On the basis of their promising profile of in vitro and in vivo activities, hydroxamic acids 24h, 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-++ +methylpropanamide (HP 977), and 25, 3-(6,11-dihydrodibenz[b,e]oxepin-2-yl)-N-hydroxy-N- methylpropanamide (P10294), were selected as developmental candidates for the topical treatment of inflammatory skin disorders.

Inhibitors of acyl-CoA: cholesterol acyltransferase. II. Preparation and hypocholesterolemic activity of optically active dibenz[b,e]oxepin-11-carboxanilides.

In a previous paper, we reported a novel inhibitor of acyl-CoA: cholesterol acyltransferase (ACAT), 2-bromo-N-(2,6-diisopropylphenyl)-6,11- dihydrodibenz[b,e]oxepin-11-carboxamide (1). In this work, we prepared both enantiomers and tested them for ability to inhibit ACAT (liver microsomes from cholesterol-fed rabbits) in vitro and to decrease serum total cholesterol in cholesterol-fed golden hamsters in vivo. The precursor carboxylic acid 4 was optically resolved with cinchonidine. The obtained (-)- and (+)-4 were converted to (-)- and (+)-1 without racemization, respectively. The enantiomer (-)-1 showed potent ACAT inhibitory activity in vitro with an IC50 value of 8 nM and was approximately 10-fold more active than (+)-1. Furthermore, (-)-1 showed strong hypocholesterolemic activity in vivo, whereas (+)-1 was inactive. A molecular modeling study showed that the difference of ACAT inhibitory activity between the enantiomers was derived from the spatial alignment of the bromine. Compound (-)-1 was selected for further evaluation as KW-3033.

Novel angiotensin II receptor antagonists. Design, synthesis, and in vitro evaluation of dibenzo[a,d]cycloheptene and dibenzo[b,f]oxepin derivatives. Searching for bioisosteres of biphenylyltetrazole using a three-dimensional search technique.

Three-dimensional substructure searching (3D search), using the program MACCS-3D, was utilized for designing novel angiotensin II receptor antagonists which contain a bioisostere of the biphenylyltetrazole moiety of DuP 753. A 3D query was prepared from an overlay model of substructures of several potent AII antagonists. The search system retrieved 139 compounds from the database MDDR-3D, which consisted of 29,400 medicinal patent compounds. A tricyclic compound was selected from the retrieved compounds and then evolved by considering steric fitness to the overlay model and synthetic feasibility. Finally, various novel AII antagonists having dibenzo[a,d]cycloheptene or dibenzo[b,f]oxepin were designed and synthesized. The receptor binding activity (Ki) for several members of this series was in the 10(-10) M range, demonstrating the ability of 3D search technique to explore new lead structures.

Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Synthesis and hypocholesterolemic activity of dibenz[b,e]oxepin-11-carboxanilides.

A series of N-phenyl-6,11-dihydrodibenz[b,e]oxepin-11-carboxamides and related derivatives were prepared on the basis of structures of the reported inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). These compounds were tested for their ability to inhibit ACAT (liver microsomes from cholesterol-fed rabbits) in vitro and to decrease serum total cholesterol in cholesterol-fed golden hamsters in vivo. The structure-activity relationships in vitro were as follows. Substitution at positions 2 and 6 in the anilide resulted in potent inhibitory activity, and the potency increased with increasing size of the substituents, with maximum potency being obtained with a 2,6-diisopropyl substitution. The position of the substituent on the dibenz[b,e]oxepin ring system influenced the activity, and substitution at position 2 was critical for potent activity. The electronic effect of the substituent at position 2 does not influence activity, but bulkiness seems to be a significant factor. The lipophilicity of the compounds also plays an important role in determining ACAT inhibitory activity. Among the compounds tested, 2-bromo-N-(2,6-diisopropylphenyl)-6,11-dihydrodibenz-[b,e]++ +oxepin-11- carboxamide (33, KF17828) showed significant in vitro activity (rabbit liver microsomes IC50 = 23 nM) and the most potent in vivo activity (complete reduction in elevated serum total cholesterol levels at a dose of 10 mg/kg in hamsters).

New hexahydroxybiphenyl derivatives as inhibitors of protein kinase C.

We have previously shown that some ellagitannins are potent inhibitors of protein kinase C (PKC). On the basis of this finding, several series of hexahydroxybiphenyl derivatives of ellagic acid were synthesized as simple analogs of these ellagitannins and were evaluated for their inhibitory effect against PKC. Compounds 23 and 26 were found to be potent inhibitors of PKC, while hexakis-(benzyloxy)biphenyl derivatives exhibited weak anti-PKC activity.

Enzymatic optical resolution of dibenzoxepins and its application to an optically active antiallergic agent with thromboxane A2 receptor antagonistic activity.

Methyl (+/-)-11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin- 2- carboxylate (5) was enantio-selectively acylated with acetic anhydride in an organic medium by Lipase Amano P to give methyl (-)-11-(2-acetoxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2- carboxylate (8), and the (+)-enantiomer by Lipase Sigma Type VII. Using Lipase Amano P, (+)- and (-)-(5) could be prepared with high optical purity (84-94% e.e.). These products were respectively converted to (+)- and (-)-KW-4099, which had antiallergic activity with complete retention of the optical purity.

Dibenzoxepin derivatives: thromboxane A2 synthase inhibition and thromboxane A2 receptor antagonism combined in one molecule.

A new series of 6,11-dihydrodibenz[b,e]oxepin derivatives exerting both thromboxane synthase inhibitory (TXS-I) and thromboxane receptor antagonist (TXRA) activities is described. (-)-11-[(3-Pyridylmethyl)thio]-6,11-dihydrodibenz[b,e]oxepin -2- carboxylic acid [(-)-3] and (E)-11-[2-(3-pyridyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin+ ++-2- carboxylic acid methanesulfonate (11E) exhibited potent inhibitory effects on bovine platelet thromboxane synthase with IC50 values of 4.0 and 14 nM, respectively, and these derivatives also antagonized guinea pig platelet TXA2/PGH2 receptors with Ki values of 85 and 180 nM, respectively. Compound 11E exhibited the dual inhibitory activity in ex vivo experiments and demonstrated a significant protective effect in a rat acute renal failure model.

Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives.

A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents. These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agent. Most compounds synthesized exhibited potent inhibitory effects on 48-h homologous passive cutaneous anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea pigs. Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenz[b,e]oxepin ring system exhibited inhibitory effects on specific [3H]pyrilamine binding to guinea pig cerebellum histamine H1 receptors, whereas these demonstrated negligible effects on specific [3H]QNB binding to rat striatum muscarinic acetylcholine M1 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system. Among the compounds synthesized, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride (16) was selected for further evaluation. It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs. Furthermore, it had a Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po. Compound 16 is now under clinical evaluation as KW-4679.

Synthesis and optical resolution of an antiallergic agent KW4099 with thromboxane A2 antagonistic activity.

A new antiallergic agent with thromboxane A2 antagonistic activity, KW4099, was synthesized by a simple method. Its optical resolution was accomplished with the use of (+)- or (-)-2,2'-(1,1'-binaphthyl)phosphoric acid as a resolving agent.