The use of alcohols and unsaturated reactants for the redox‐triggered generation of nucleophile–electrophile pairs represents a broad, new approach to carbonyl addition chemistry. Discrete redox manipulations that are often required for the generation of carbonyl electrophiles and premetalated carbon‐centered nucleophiles are thus avoided. Based on this concept, a broad, new family of enantioselective CC coupling reactions that are catalyzed by iridium or ruthenium complexes have been developed, which are summarized in this Minireview.
The PRMT5•MTA
complex has recently emerged as a new synthetically
lethal drug target for the treatment of MTAP-deleted
cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective
binder to the PRMT5•MTA complex and selectively inhibits PRMT5
activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent
inhibition of PRMT5-dependent symmetric dimethylarginine protein modification
in MTAP-deleted tumors that correlated with antitumor
activity. A 4-(aminomethyl)phthalazin-1(2H)-one hit
was identified through a fragment-based screen, followed by X-ray
crystallography, to confirm binding to the PRMT5•MTA complex.
Fragment growth supported by structural insights from X-ray crystallography
coupled with optimization of pharmacokinetic properties aided the
discovery of development candidate MRTX1719.
SOS1 is one of the major guanine nucleotide exchange
factors that
regulates the ability of KRAS to cycle through its “on”
and “off” states. Disrupting the SOS1:KRAS
G12C
protein–protein interaction (PPI) can increase the proportion
of GDP-loaded KRAS
G12C
, providing a strong mechanistic
rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors
like MRTX849 that target GDP-loaded KRAS
G12C
. In this report,
we detail the design and discovery of MRTX0902—a potent, selective,
brain-penetrant, and orally bioavailable SOS1 binder that disrupts
the SOS1:KRAS
G12C
PPI. Oral administration of MRTX0902
in combination with MRTX849 results in a significant increase in antitumor
activity relative to that of either single agent, including tumor
regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft
model.
The Au(I)-catalyzed intermolecular hydroalkoxylation of alkynes with allylic alcohols to provide allyl vinyl ethers that subsequently undergo Claisen rearrangement is reported. This new cascade reaction strategy facilitates the direct formation of γ,δ-unsaturated ketones from simple starting materials in a single step.
The seco-B-ring
bryostatin analogue, macrodiolide WN-1, was prepared
in 17 steps (longest linear sequence) and
30 total steps with three bonds formed via hydrogen-mediated C–C
coupling. This synthetic route features a palladium-catalyzed alkoxycarbonylation
of a C2-symmetric diol to form the C9-deoxygenated
bryostatin A-ring. WN-1 binds to PKCα (Ki = 16.1 nM) and inhibits the growth of multiple
leukemia cell lines. Although structural features of the WN-1 A-ring and C-ring are shared by analogues that display bryostatin-like
behavior, WN-1 displays PMA-like behavior in U937 cell
attachment and proliferation assays, as well as in K562 and MV-4-11
proliferation assays. Molecular modeling studies suggest the pattern
of internal hydrogen bonds evident in bryostatin 1 is preserved in WN-1, and that upon docking WN-1 into the crystal
structure of the C1b domain of PKCδ, the binding mode of bryostatin
1 is reproduced. The collective data emphasize the critical contribution
of the B-ring to the function of the upper portion of the molecule
in conferring a bryostatin-like pattern of biological activity.
The synthesis and biological evaluation of chromane-containing bryostatin analogues WN-2 to WN-7 and the previously reported salicylate-based analogue WN-8 are described. Analogues WN-2 to WN-7 are prepared through convergent assembly of the chromane-containing Fragment B-I with the “binding domain” Fragment A-I or its C26-des-methyl congener, Fragment A-II. The synthesis of Fragment B-I features enantioselective double C-H allylation of 1,3-propane diol to form the C2-symmetric diol 3 and Heck cyclization of bromodiene 5 to form the chromane core. The synthesis of salicylate WN-8 is accomplished through the union of Fragments A-III and B-II. The highest binding affinities for PKCα are observed for the C26-des-methyl analogues WN-3 (Ki = 63.9 nM) and WN-7 (Ki = 63.1 nM). All analogues, WN-2 to WN-8, inhibited growth of Toledo cells, with the most potent analogue being WN-7. This response, however, does not distinguish between phorbol ester-like and bryostatin-like behavior. In contrast, while many of the analogues contain a conserved C-ring in the binding domain and other features common to analogues with bryostatin-like properties, all analogues evaluated in the U937 proliferation and cell attachment assays displayed phorbol ester-like and/or toxic behavior, including WN-8, for which “bryostatin-like PKC modulatory activities” previously was suggested solely based on PKC binding. These results underscore the importance of considering downstream biological effects, as tumor suppression cannot be inferred from potent PKC binding.
Recruitment of suppressive CD4+ FOXP3+ regulatory
T cells (Treg) to the tumor microenvironment (TME) has
the potential to weaken the antitumor response in patients receiving
treatment with immuno-oncology (IO) agents. Human Treg express
CCR4 and can be recruited to the TME through the CC chemokine ligands
CCL17 and CCL22. In some cancers, Treg accumulation correlates
with poor patient prognosis. Preclinical data suggests that preventing
the recruitment of Treg and increasing the population of
activated effector T cells (Teff) in the TME can potentiate
antitumor immune responses. We developed a novel series of potent,
orally bioavailable small molecule antagonists of CCR4. From this
series, several compounds exhibited high potency in distinct functional
assays in addition to good in vitro and in vivo ADME properties. The
design, synthesis, and SAR of this series and confirmation of its
in vivo activity are reported.
A novel gold-catalyzed synthesis of unsaturated spiroketals that addresses regioselectivity issues commonly reported in metal-catalyzed spiroketalization of alkynes is reported. The reaction sequence is regulated by an acetonide protecting group which undergoes extrusion of acetone to deliver the desired spiroketals in good yields and diastereoselectivities. The reaction, which is carried out under very mild conditions employing AuCl as the catalyst, should be widely applicable in the synthesis of a broad range of spiroketals.
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