8 research outputs found
Total Synthesis of (−)-Irciniastatin B and Structural Confirmation via Chemical Conversion to (+)-Irciniastatin A (Psymberin)
The total synthesis and structural confirmation of the marine sponge cytotoxin (−)-irciniastatin B has been achieved via a unified strategy employing a late-stage, selective deprotection/oxidation sequence that provides access to both (+)-irciniastatin A (psymberin) and (−)-irciniastatin B
The Design, Synthesis and Validation of Recoverable and Readily Reusable Siloxane Transfer Agents for Pd-Catalyzed Cross-Coupling Reactions
The development of competent, recoverable and reusable 1-oxa-2-silacyclopentene
(siloxane) transfer agents for Pd-catalyzed cross-coupling reactions
(CCRs) of organolithium reagents with aryl and alkenyl iodides has
been achieved. Drawbacks of the first-generation siloxane-transfer
agent (<b>1</b>), relating to facile recovery for potential
recycling, have been addressed
The Design, Synthesis and Validation of Recoverable and Readily Reusable Siloxane Transfer Agents for Pd-Catalyzed Cross-Coupling Reactions
The development of competent, recoverable and reusable 1-oxa-2-silacyclopentene
(siloxane) transfer agents for Pd-catalyzed cross-coupling reactions
(CCRs) of organolithium reagents with aryl and alkenyl iodides has
been achieved. Drawbacks of the first-generation siloxane-transfer
agent (<b>1</b>), relating to facile recovery for potential
recycling, have been addressed
Total Synthesis of (+)-Irciniastatin A (a.k.a. Psymberin) and (−)-Irciniastatin B
A unified synthetic strategy to access
(+)-irciniastatin A (a.k.a.
psymberin) and (−)-irciniastatin B, two cytotoxic secondary
metabolites, has been achieved. Highlights of the convergent strategy
comprise a boron-mediated aldol union to set the C(15)–C(17) <i>syn–syn</i> triad, reagent control to set the four stereocenters
of the tetrahydropyran core, and a late-stage Curtius rearrangement
to install the acid-sensitive stereogenic <i>N</i>,<i>O</i>-aminal. Having achieved the total synthesis of (+)-irciniastatin
A, we devised an improved synthetic route to the tetrahydropyran core
(13 steps) compared to the first-generation synthesis (22 steps).
Construction of the structurally similar (−)-irciniastatin
B was then achieved via modification of a late-stage (−)-irciniastatin
A intermediate to implement a chemoselective deprotection/oxidation
sequence to access the requisite oxidation state at C(11) of the tetrahydropyran
core. Of particular significance, the unified strategy will permit
late-stage diversification for analogue development, designed to explore
the biological role of substitution at the C(11) position of these
highly potent tumor cell growth inhibitory molecules
Design, Synthesis, and Evaluation of Irciniastatin Analogues: Simplification of the Tetrahydropyran Core and the C(11) Substituents
The
design, synthesis, and biological evaluation of irciniastatin
A (<b>1</b>) analogues, achieved by removal of three synthetically
challenging structural units, as well as by functional group manipulation
of the C(11) substituent of both irciniastatins A and B (<b>1</b> and <b>2</b>), has been achieved. To this end, we first designed
a convergent synthetic route toward the diminutive analogue (+)-<i>C</i>(8)-desmethoxy-<i>C</i>(11)-deoxy-<i>C</i>(12)-didesmethylirciniastatin (<b>6</b>). Key transformations
include an acid-catalyzed 6-<i>exo</i>-tet pyran cyclization,
a chiral Lewis acid mediated aldol reaction, and a facile amide union.
The absolute configuration of <b>6</b> was confirmed via spectroscopic
analysis (CD spectrum, HSQC, COSY, and ROESY NMR experiments). Structure–activity
relationship (SAR) studies of <b>6</b> demonstrate that the
absence of the three native structural units permits access to analogues
possessing cytotoxic activity in the nanomolar range. Second, manipulation
of the C(11) position, employing late-stage synthetic intermediates
from our irciniastatin syntheses, provides an additional five analogues
(<b>7</b>–<b>11</b>). Biological evaluation of
these analogues indicates a high functional group tolerance at position
C(11)
Facile Route to 2‑Fluoropyridines via 2‑Pyridyltrialkylammonium Salts Prepared from Pyridine <i>N</i>‑Oxides and Application to <sup>18</sup>F‑Labeling
Among
known precursors for 2-[<sup>18</sup>F]Âfluoropyridines, pyridyltrialkylammonium
salts have shown excellent reactivity; however, their broader utility
has been limited because synthetic methods for their preparation suffer
from poor functional group compatibility. In this paper, we demonstrate
the regioselective conversion of readily available pyridine <i>N</i>-oxides into 2-pyridyltrialkylammonium salts under mild
and metal-free conditions. These isolable intermediates serve as effective
precursors to structurally diverse 2-fluoropyridines, including molecules
relevant to PET imaging. In addition to providing access to nonradioactive
analogues, this method has been successfully applied to <sup>18</sup>F-labeling in the radiosynthesis of [<sup>18</sup>F]ÂAV-1451 ([<sup>18</sup>F]ÂT807), a PET tracer currently under development for imaging
tau
[<sup>18</sup>F]FluorobenzoylÂlysineÂpentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA)
Radiolabeled urea-based low-molecular
weight inhibitors of the
prostate-specific membrane antigen (PSMA) are under intense investigation
as imaging and therapeutic agents for prostate and other cancers.
In an effort to provide agents with less nontarget organ uptake than
the ureas, we synthesized four <sup>18</sup>F-labeled inhibitors of
PSMA based on carbamate scaffolds. 4-Bromo-2-[<sup>18</sup>F]ÂfluorobenzoylÂlysineoxyÂpentanedioic
acid (OPA) carbamate [<sup>18</sup>F]<b>23</b> and 4-iodo-2-[<sup>18</sup>F]ÂfluorobenzoylÂlysine OPA carbamate [<sup>18</sup>F]<b>24</b> in particular exhibited high target-selective uptake in
PSMA+ PC3 PIP tumor xenografts, with tumor-to-kidney ratios of >1
by 4 h postinjection, an important benchmark. Because of its high
tumor uptake (90% injected dose per gram of tissue at 2 h postinjection)
and high tumor-to-organ ratios, [<sup>18</sup>F]<b>23</b> is
promising for clinical translation. Prolonged tumor-specific uptake
demonstrated by [<sup>18</sup>F]<b>24</b>, which did not reach
equilibrium during the 4 h study period, suggests carbamates as alternative
scaffolds for mitigating dose to nontarget tissues
Brain-Penetrant, Orally Bioavailable Microtubule-Stabilizing Small Molecules Are Potential Candidate Therapeutics for Alzheimer’s Disease and Related Tauopathies
Microtubule
(MT) stabilizing drugs hold promise as potential treatments
for Alzheimer’s disease (AD) and related tauopathies. However,
thus far epothilone D has been the only brain-penetrant MT-stabilizer
to be evaluated in tau transgenic mice and in AD patients. Furthermore,
this natural product exhibits potential deficiencies as a drug candidate,
including an intravenous route of administration and the inhibition
of the P-glycoprotein (Pgp) transporter. Thus, the identification
of alternative CNS-active MT-stabilizing agents that lack these potential
limitations is of interest. Toward this objective, we have evaluated
representative compounds from known classes of non-naturally occurring
MT-stabilizing small molecules. This led to the identification of
selected triazolopyrimidines and phenylpyrimidines that are orally
bioavailable and brain-penetrant without disruption of Pgp function.
Pharmacodynamic studies confirmed that representative compounds from
these series enhance MT-stabilization in the brains of wild-type mice.
Thus, these classes of MT-stabilizers hold promise for the development
of orally active, CNS-directed MT-stabilizing therapies