Equatorial and axial hydrogens in heterocyclic six-membered rings: the rotational spectrum of piperazine

The rotational spectrum of piperazine has been investigated by free jet absorption millimeter wave spectroscopy. The spectrum of the polar conformer with axial\u2013equatorial orientations of the two amino hydrogens was only observed. This assignment was confirmed by the spectra of the two monodeuterated and the bideuterated species. Ab initio and density functional calculations predict the observed conformer to have an energy intermediate between the equatorial\u2013equatorial and axial\u2013axial non-polar forms, the former species being the global minimum

Molecular beam Fourier transform microwave spectrum of the dimethylether-xenon complex: tunnelling splitting and 131Xe quadrupole coupling constants

The rotational spectra of three isotopomers of the complex dimethyl ether–Xe (132Xe, 129Xe, 131Xe) have been measured by molecular beam Fourier transform microwave spectroscopy. An evenly spaced doubling of ca. 0.2 MHz, due to the internal rotation of the dimethyl ether subunit in the complex, has been observed for the lc-type transitions. The corresponding vibrational spacing, D01, has been determined to be 105(1) and 106(1) kHz for the 132Xe and 129Xe species, respectively. This datum has been useful to size the tunnelling barrier of Xe from above to below the COC plane. The nuclear quadrupole coupling constants of the 131Xe ðI ¼ 3=2Þ species have been precisely determined, vaa ¼ 4:57ð3Þ, vbb ¼ 2:93ð3Þ, and vcc ¼ 1:64ð3Þ MHz, respectively. These values indicate that the nuclear contributions to the field electric gradient at the Xe nucleus are smaller than the electronic ones

A Fragment-Derived Clinical Candidate for Antagonism of X‑Linked and Cellular Inhibitor of Apoptosis Proteins: 1‑(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl‑1<i>H</i>,2<i>H</i>,3<i>H</i>‑pyrrolo[3,2‑<i>b</i>]pyridin-1-yl)-2-[(2<i>R</i>,5<i>R</i>)‑5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660)

Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP–XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate <b>27</b> (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423)

A Fragment-Derived Clinical Candidate for Antagonism of X‑Linked and Cellular Inhibitor of Apoptosis Proteins: 1‑(6-[(4-Fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl‑1<i>H</i>,2<i>H</i>,3<i>H</i>‑pyrrolo[3,2‑<i>b</i>]pyridin-1-yl)-2-[(2<i>R</i>,5<i>R</i>)‑5-methyl-2-([(3R)-3-methylmorpholin-4-yl]methyl)piperazin-1-yl]ethan-1-one (ASTX660)

Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure-based optimization has previously been reported that resulted in a low-nanomolar cIAP1 and XIAP antagonist lead molecule with a more balanced cIAP–XIAP profile. We now report the further structure-guided optimization of the lead, with a view to improving the metabolic stability and cardiac safety profile, to give the nonpeptidomimetic antagonist clinical candidate <b>27</b> (ASTX660), currently being tested in a phase 1/2 clinical trial (NCT02503423)