Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.

Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these diseases are small molecules directly modulating the force produced by ß-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction.

Inherited cardiomyopathies are amongst the most common cardiac diseases worldwide, leading in the late-stage to heart failure and death. The most promising treatments against these diseases are small-molecules directly modulating the force produced by ß-cardiac myosin, the molecular motor driving heart contraction. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activator Omecamtiv mecarbil and the inhibitor Mavacamten. In this work, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing ß-cardiac myosin in the apo form or bound to Omecamtiv mecarbil or Mavacamten. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

Effects of fetal and maternal genotype on placentome morphology in sheep.

Both maternal and fetal genotypes contribute to conceptus development. The objective was to determine how placentome number, size, and type and fetal weight was influenced after reciprocal embryo transfer in Columbia and Romanov sheep. Reciprocal embryo transfer was conducted between Columbia and Romanov ewes where a single embryo was transferred into Romanov and Columbia recipients [Romanov embryo in a Romanov uterus (RinR, n = 9); Romanov embryo in a Columbia uterus (RinC, n = 7); Columbia embryo in a Columbia uterus (CinC, n = 8); Columbia embryo in a Romanov uterus (CinR, n = 4)]. On day 130 of gestation, fetuses were weighed and placentomes were morphologically typed, weighed, and measured. Regardless of maternal genotype, Romanov fetuses were smaller (P < 0.05) compared to Columbia fetuses. Moreover, CinC fetuses were larger (P < 0.05) than CinR fetuses. There was a tendency (P = 0.12) for a fetal by maternal genotype interaction on total placentome weight, but main effects were significant for fetal genotype (P = 0.04) and maternal genotype (P < 0.01). The number of Type A placentomes was greater than any other types. Type A placentomes had a greater (P < 0.05) contribution to total placentome weight within the Romanov uterus, or when associated with a Romanov fetus, than within the Columbia breed, in which placentome type was evenly distributed. The hypothesis that the Romanov uterus would limit the growth of a Columbia conceptus is accepted; however, the Romanov conceptus did not experience augmented growth when transferred into a Columbia uterus as predicted.

Synthesis of 1,1'- and 2,2'-Bicarbazole Alkaloids by Iron(III)-Catalyzed Oxidative Coupling of 2- and 1-Hydroxycarbazoles.

We describe the synthesis of 1,1'- and 2,2'-bicarbazoles by oxidative homocoupling of 2- and 1-hydroxycarbazoles. The oxidative coupling using catalytic amounts of F16 PcFe can be applied to both groups of substrates. Although F16 PcFe generally provides the best yields for the synthesis of 1,1'-bicarbazoles, di-tert-butyl peroxide affords better results for the 2,2'-bicarbazoles. In our study, we have achieved the first syntheses of the biscarbalexines A-C, bisglybomine B, 2,2'-dihydroxy-7,7'-dimethoxy-3,3'-dimethyl-1,1'-bicarbazole, bispyrayafoline C, and bisisomahanine. The iron-catalyzed coupling of koenigine led to an improved synthesis of 8,8''-biskoenigine and afforded an unprecedented decacylic product. Oxidative coupling of 1-hydroxycarbazoles led to bisclausenol, and to the first total syntheses of bismurrayafoline B and D.

Synthesis of Glycoborine, Glybomine A and B, the Phytoalexin Carbalexin A and the ß-Adrenoreceptor Antagonists Carazolol and Carvedilol.

We describe a regioselective synthesis of 4- or 5-substituted carbazoles by oxidative cyclisation of meta-oxygen-substituted N-phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4-hydroxycarbazole, a precursor for the enantiospecific synthesis of the ß-adrenoreceptor antagonists (-)-(S)-carazolol (5) and (-)-(S)-carvedilol (6). Regioselective palladium(II)-catalysed cyclisation of different diarylamines led to total synthesis of glycoborine (7) and the first total syntheses of the phytoalexin carbalexin A (8), glybomine A (9) and glybomine B (10). For glybomine B (10), a 5-hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.

Chemical constituents isolated from Zygophyllum melongena Bunge growing in Mongolia.

We report the first investigation of the chemical constituents of Zygophyllum melongena Bunge, a species growing in Mongolia. The quinovic acid glycosides 3-O-(ß-D-glucopyranosyl)quinovic acid and 3-O-(ß-D-glucopyranosyl)quinovic acid (28→1)-(ß-D-glucopyranosyl) ester were identified in the chloroform fraction along with the flavonoid glycoside astragalin. The n-butanol fraction contained (+)-D-pinitol as the major component, a cyclitol with anti-diabetic properties. The structures of the isolated natural products were confirmed using ESI-MS and NMR spectroscopy ((1)H, (13)C, COSY, HSQC, HMBC, NOESY and ROESY). This is the first report of the isolation of (+)-D-pinitol from the genus Zygophyllum.

Synthesis of Methylene-Bridged Biscarbazole Alkaloids by using an Ullmann-type Coupling: First Total Synthesis of Murrastifoline-C and Murrafoline-E.

We describe the total synthesis of methylene-bridged biscarbazole alkaloids by using a late-stage Ullmann-type coupling of fully functionalised carbazole subunits. The carbazole derivatives were synthesised via a sequence of palladium(0)- and palladium(II)-catalysed coupling reactions. Our approach has provided bismurrayafoline-A, bismurrayafolinol, chrestifolines B-D, and the first total synthesis of murrastifoline-C and murrafoline-E.

Total syntheses of murrayamine E, I, and K.

We describe efficient synthetic routes to murrayamine A (mukoenine C), O-methylmurrayamine A, mahanine, O-methylmahanine, and murrayamine D and the first total syntheses of murrayamine E, I, and K. Key steps are a palladium-catalyzed construction of the carbazole framework and an annulation of the pyran ring, which is either catalyzed by phenylboronic acid or promoted by a Lewis acid.

Total synthesis of the cyclic monoterpenoid pyrano[3,2-a]carbazole alkaloids derived from 2-hydroxy-6-methylcarbazole.

The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic precursor 2-hydroxy-6-methylcarbazole as key intermediate.

Synthesis of prenyl- and geranyl-substituted carbazole alkaloids by DIBAL-H promoted reductive pyran ring opening of dialkylpyrano[3,2-a]carbazoles.

The DIBAL-H promoted reductive pyran ring opening of dialkylpyrano[3,2-a]carbazoles provides a direct access to a broad range of prenyl- and geranyl-substituted carbazoles. Formation of a pyran ring followed by reductive ring opening represents a new method for the introduction of prenyl and geranyl groups. In the course of the present work, we achieved the first total syntheses of the following eight carbazole alkaloids: clauraila-E, 7-hydroxyheptaphylline, 7-methoxyheptaphylline, mukoenine-B (clausenatine-A), mukoenine-A (girinimbilol), mahanimbinol (mahanimbilol), euchrestine-A, and isomurrayafoline-B.

Total synthesis of 7- and 8-oxygenated pyrano[3,2-a]carbazole and pyrano[2,3-a]carbazole alkaloids via boronic acid-catalyzed annulation of the pyran ring.

The boronic acid-catalyzed annulation of citral opens up a short route to oxygenated cyclized monoterpenoid pyranocarbazole alkaloids. Thus, murrayamine-D is available in only three steps and 55% overall yield from the corresponding carbazole precursor.

First total syntheses of chrestifoline-B and (±)-chrestifoline-C, and improved synthetic routes to bismurrayafoline-A, bismurrayafolinol and chrestifoline-D.

We describe an efficient synthesis of the methylene-bridged biscarbazole alkaloids bismurrayafoline-A, bismurrayafolinol and chrestifoline B-D using an Ullmann-type coupling at the benzylic position.

Palladium(II)-catalysed total synthesis of naturally occurring pyrano[3,2-a]carbazole and pyrano[2,3-b]carbazole alkaloids.

Seven naturally occurring pyranocarbazole alkaloids (pyrayafoline A-E, O-methylmurrayamine A and O-methylmahanine) have been obtained by total synthesis using a palladium(II)-catalysed oxidative cyclisation of a diarylamine to an orthogonally diprotected 2,7-dihydroxycarbazole as key step.

Regioselective prenylation of bromocarbazoles by palladium(0)-catalysed cross coupling--synthesis of O-methylsiamenol, O-methylmicromeline and carquinostatin A.

We describe the regioselective prenylation of 3-bromocarbazole by palladium(0)-catalysed cross coupling with a prenylstannane or a prenylboronate. The procedure is applied to the synthesis of precursors for biologically active carbazole alkaloids.

Inhibitory effect of oxygenated cholestan-3ß-ol derivatives on the growth of Mycobacterium tuberculosis.

A variety of cholestan-3ß-ol derivatives, which are oxygenated at different positions of the steroid ring system, were prepared and tested for their inhibition of the Mycobacterium tuberculosis H37Rv strain. Several compounds showed significant antitubercular activities with MIC90 values in the range 4-8 µM and low or non-detectable toxicity against mammalian cells.

Efficient construction of pyrano[3,2-a]carbazoles: application to a biomimetic total synthesis of cyclized monoterpenoid pyrano[3,2-a]carbazole alkaloids.

We have developed a highly efficient route to 2-hydroxy-3-methylcarbazole (1) via a palladium-catalyzed construction of the carbazole skeleton. Using 1 as relay compound, different methods for annulations of pyran rings by reaction with terpenoid building blocks have been tested. The Lewis acid promoted reaction of 1 with prenal (21) opened up an efficient route to girinimbine (3) and the corresponding reaction with citral (25) afforded mahanimbine (5). Oxidation of compounds 3 and 5 provided murrayacine (4) and murrayacinine (6). Following the biogenetic proposal, mahanimbine (5) has been exploited for efficient biomimetic syntheses of the cyclized monoterpenoid pyrano[3,2-a]carbazole alkaloids cyclomahanimbine (7), mahanimbidine (8) and bicyclomahanimbine (9). The interconversions of 5, 7, 8 and 9 are described and mechanistic implications are discussed. Structural assignments are unambiguously verified by X-ray crystal structure determinations. Moreover, cyclomahanimbine (7) was transformed into murrayazolinine (10) and exozoline (11).

Synthesis and biological activity of (24E)- and (24Z)-26-hydroxydesmosterol.

Using 3ß-hydroxychol-5-en-24-oic acid (4) as starting material, the diastereoisomeric allylic alcohols (24E)-26-hydroxydesmosterol (2) and (24Z)-26-hydroxydesmosterol (3) have been synthesised in six steps with 67% and 12% overall yield, respectively. Both of these isomers are found in newborn mouse brain where sterol synthesis is high. Unlike desmosterol (1), neither of these isomers is a ligand to the liver x receptors and thus represents a novel biological deactivation mechanism avoiding cholesterol synthesis.

Stereoselective synthesis and hormonal activity of novel dafachronic acids and naturally occurring steroids isolated from corals.

A stereoselective synthesis of (25S)-Δ(1)-, (25S)-Δ(1,4)-, (25S)-Δ(1,7)-, (25S)-Δ(8(14))-, (25S)-Δ(4,6,8(14))-dafachronic acid, methyl (25S)-Δ(1,4)-dafachronate and (25S)-5α-hydroxy-3,6-dioxocholest-7-en-26-oic acid is described. (25S)-Δ(1,4)-Dafachronic acid and its methyl ester are natural products isolated from corals and have been obtained by synthesis for the first time. (25S)-5α-Hydroxy-3,6-dioxocholest-7-en-26-oic acid represents a promising synthetic precursor for cytotoxic marine steroids.

Organosilicon-mediated total synthesis of the triquinane sesquiterpenes (±)-ß-isocomene and (±)-isocomene.

We describe an efficient total synthesis of the sesquiterpenes (±)-ß-isocomene and (±)-isocomene using a Lewis acid-promoted [3 + 2] cycloaddition of allyl-tert-butyldiphenylsilane as the key-step.