Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy.

The mandelalides comprise a family of structurally complex marine macrolides that display significant cytotoxicity against several human cancer cell lines. Presented here is a full account on the development of an Anion Relay Chemistry (ARC) strategy for the total synthesis of (-)-mandelalides A and L, the two most potent members of the mandelalide family. The design and implementation of a three-component type II ARC/cross-coupling protocol and a four-component type I ARC union permits rapid access respectively to the key tetrahydrofuran and tetrahydropyran structural motifs of these natural products. Other highlights of the synthesis include an osmium-catalyzed oxidative cyclization of an allylic 1,3-diol, a mild Yamaguchi esterification to unite the northern and southern hemispheres, and a late-stage Heck macrocyclization. Synthetic mandelalides A and L displayed potent cytotoxicity against human HeLa cervical cancer cells (EC50, 1.3 and 3.1 nM, respectively). This synthetic approach also provides access to several highly potent non-natural mandelalide analogs, including a biotin-tagged mandelalide probe for future biological investigation.

Total Synthesis of (-)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC/CuCN Cross-Coupling Protocol.

Anion relay chemistry (ARC), an effective, multicomponent union tactic, was successfully employed for the total synthesis of the highly cytotoxic marine macrolide (-)-mandelalide A (1). The northern hemisphere was constructed via a new type II ARC/CuCN cross-coupling tactic, while the southern hemisphere was secured via a highly efficient four-component type I ARC union. Importantly, the synthesis of 1 showcases ARC as a rapid, scalable coupling strategy for the union of simple readily available building blocks to access diverse complex molecular fragments with excellent stereochemical control.

Calcium phosphate controls nucleation and growth of calcium oxalate crystal phases in kidney stones.

Kidney stone disease is a serious disease due to the severe pain it causes, high morbidity, and high recurrence rate. Notably, calcium oxalate stones are the most common type of kidney stone. Calcium oxalate appears in two forms in kidney stones: the stable phase, monohydrate (COM), and the metastable phase, dihydrate (COD). Particularly, COM stones with concentric structures are hard and difficult to treat. However, the factor determining the growth of either COM or COD crystals in the urine, which is supersaturated for both phases, remains unclear. This study shows that calcium phosphate ingredients preferentially induce COM crystal nucleation and growth, by observing and analyzing kidney stones containing both COM and COD crystals. The forms of calcium phosphate are not limited to Randall's plaques (1-2 mm size aggregates, which contain calcium phosphate nanoparticles and proteins, and form in the renal papilla). For example, aggregates of strip-shaped calcium phosphate crystals and fields of dispersed calcium phosphate microcrystals (nano to micrometer order) also promote the growth of concentric COM structures. This suggests that patients who excrete urine with a higher quantity of calcium phosphate crystals may be more prone to forming hard and troublesome COM stones.

Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the beta2-adrenergic receptor: part 6.

As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.

Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I.

A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.

Discovery of novel series of benzoic acid derivatives containing biphenyl ether moiety as potent and selective human beta(3)-adrenergic receptor agonists: Part IV.

Identification and SAR study of novel series of beta(3)-AR agonists with benzoic acid are described. Conversion of ether linkage position of phenoxybenzoic acid derivative 2b led to compound 7b with moderate beta(3)-AR activity. Further modification in right, center and left parts of compound 7b was investigated to improve the beta(3)-AR potency and selectivity. Compounds 7g and 7k, with the bulky aliphatic-substituted group at 2-position of benzoic acid moiety, were identified as potent and selective beta(3)-AR agonists. In addition, in vivo efficacy of compounds 7g and 7k was exhibited on dog OAB model.

Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and evaluation of physical properties as potential overactive bladder therapies: part 5.

As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC(50) values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve beta(3) activity.

Discovery of a novel series of benzoic acid derivatives as potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety.

We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys.

Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. Part II.

The left-hand side (LHS) and central part of our first generation biphenyl (FGB) series was modified to improve in vitro and in vivo beta3-AR potency without loss of oral bioavailability. First, in this study, we focused our efforts on replacement of the 3-chlorophenyl moiety in the LHS of FGB analogues with 3-pyridyl ring analogues to adjust the lipophilicity. Second, we investigated the replacement of the central part of this series and discovered that introduction of a methyl group into the alpha-position of the phenethylamine moiety greatly enhanced potency keeping good oral availability. Finally, the replacement of the two carbon linker of the central part with an ethoxy-based linker provided improved potency and PK profiles. As a result of these studies, several analogues (i.e., 9h, 9k, 9l, 10g, 10m, 10p, 10r, 11b, and 11l) were identified that displayed an excellent balance of very higher human beta3-AR potency compared to the FGB compounds, high selectivity, and good pharmacokinetic profiles. Furthermore, these several compounds showed high in vivo efficacy in an overactive bladder (OAB) model. These findings suggest that our selected second generation biphenyl (SGB) series compounds may be attractive new successful therapeutic candidates for the treatment of OAB.

Lipase-catalyzed domino kinetic resolution/intramolecular Diels-Alder reaction: one-pot synthesis of optically active 7-oxabicyclo[2.2.1]heptenes from furfuryl alcohols and beta-substituted acrylic acids.

The first lipase-catalyzed domino reaction is described in which the acyl moiety formed during the enzymatic kinetic resolution of furfuryl alcohols (+/-)-3 with a 1-ethoxyvinyl ester 2 was utilized as a part of the constituent structure for the subsequent Diels-Alder reaction. The preparation of ester 2 from carboxylic acid 1 and the subsequent domino reaction were carried out in a one-pot reaction. Therefore, this procedure provides a convenient preparation of the optically active 7-oxabicyclo[2.2.1]heptene derivatives 5, which has five chiral, non-racemic carbon centers, from achiral 1 and racemic 3. The overall efficiency of this process was dependent on the substituent at the C-3 position of 3, and the use of the 3-methylfurfuryl derivatives, (+/-)-3 b and (+/-)-3 f, exclusively produced diastereoselectivity with excellent enantioselectivity to give (2R)-syn-5 (91->/=99 % ee) and (S)-3 (96->/=99 % ee). Similar procedures starting from the 3-bromofurfuryl alcohols (+/-)-3 h-j provided the cycloadducts (2R)-syn-5 j-q (93->/=99 % ee), in which the bromo group was utilized for the installation of bulky substituents to the 7-oxabicycloheptene core.