22 research outputs found
Synthesis of Chamaecypanone C Analogues from <i>in Situ</i>-Generated Cyclopentadienones and Their Biological Evaluation
A rhodium-catalyzed dehydrogenation protocol for the
conversion
of 3,5-diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones
has been developed. With this protocol, analogues of the cytotoxic
agent chamaecypanone C have been synthesized <i>via</i> Diels–Alder
cycloaddition between the cyclopentadienones and <i>in situ</i>-generated <i>o</i>-quinols. Biological evaluation of these analogues revealed
a compound with higher activity as a microtubule inhibitor and cytotoxic
agent in comparison with the parent structure
Synthesis of Chamaecypanone C Analogues from <i>in Situ</i>-Generated Cyclopentadienones and Their Biological Evaluation
A rhodium-catalyzed dehydrogenation protocol for the
conversion
of 3,5-diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones
has been developed. With this protocol, analogues of the cytotoxic
agent chamaecypanone C have been synthesized <i>via</i> Diels–Alder
cycloaddition between the cyclopentadienones and <i>in situ</i>-generated <i>o</i>-quinols. Biological evaluation of these analogues revealed
a compound with higher activity as a microtubule inhibitor and cytotoxic
agent in comparison with the parent structure
Development of a Novel Class of Tubulin Inhibitor from Desmosdumotin B with a Hydroxylated Bicyclic B‑Ring
A series
of newly synthesized hydroxylated analogues of triethyldesmosdumotin
B (TEDB) with a bicyclic B-ring exhibited a significantly different
mode of action for affecting microtubule dynamics and spindle formation
but had the same antiproliferative activity spectrum, including activity
against multidrug-resistant tumors. These analogues efficiently induced
cell cycle arrest at prometaphase and caused formation of immature
multipolar spindles. 6′-Hydroxyl TEDB-TB (<b>8</b>) disrupted
bipolar spindle formation but had a negligible effect on interphase
microtubules. On the basis of the predicted binding modes of the new
compounds with tubulin dimer, compound <b>4</b> forms three
hydrogen bonds (H-bonds) only with α-tubulin at the colchicine
site; in contrast, <b>8</b> forms H-bonds with both α-
and β-tubulin. We predict that, when a compound/ligand, such
as <b>8</b>, forms H-bonds to both α- and β-tubulins,
spindle formation is disrupted more than the dynamics of interphase
microtubules. This result may reflect the well-known greater dynamicity
of spindle microtubules as compared with interphase microtubules
Structure–Activity Relationship and in Vitro and in Vivo Evaluation of the Potent Cytotoxic Anti-microtubule Agent <i>N</i>‑(4-Methoxyphenyl)‑<i>N</i>,2,6-trimethyl-6,7-dihydro‑5<i>H</i>‑cyclopenta[<i>d</i>]pyrimidin-4-aminium Chloride and Its Analogues As Antitumor Agents
A series
of 21 substituted cyclopentaÂ[<i>d</i>]Âpyrimidines
were synthesized as an extension of our discovery of the parent compound
(±)-<b>1</b>·HCl as an anti-microtubule agent. The
structure–activity relationship indicates that the <i>N</i>-methyl and a 4<i>N</i>-methoxy groups appear
important for potent activity. In addition, the 6-substituent in the
parent analogue is not necessary for activity. The most potent compound <b>30</b>·HCl was a one to two digit nanomolar inhibitor of
most tumor cell proliferations and was up to 7-fold more potent than
the parent compound (±)-<b>1</b>·HCl. In addition, <b>30</b>·HCl inhibited cancer cell proliferation regardless
of Pgp or βIII-tubulin status, both of which are known to cause
clinical resistance to several anti-tubulin agents. In vivo efficacy
of <b>30</b>·HCl was demonstrated against a triple negative
breast cancer xenograft mouse model. Compound <b>30</b>·HCl
is water-soluble and easily synthesized and serves as a lead compound
for further preclinical evaluation as an antitumor agent
Novel 3‑Substituted 7‑Phenylpyrrolo[3,2‑<i>f</i>]quinolin-9(6<i>H</i>)‑ones as Single Entities with Multitarget Antiproliferative Activity
A series of chemically modified 7-phenylpyrroloÂ[3,2-<i>f</i>]Âquinolinones was synthesized and evaluated as anticancer
agents.
Among them, the most cytotoxic (subnanomolar GI<sub>50</sub> values)
amidic derivative <b>5f</b> was shown to act as an inhibitor
of tubulin polymerization (IC<sub>50</sub>, 0.99 μM) by binding
to the colchicine site with high affinity. Moreover, <b>5f</b> induced cell cycle arrest in the G2/M phase of the cell cycle in
a concentration dependent manner, followed by caspase-dependent apoptotic
cell death. Compound <b>5f</b> also showed lower toxicity in
nontumoral cells, suggesting selectivity toward cancer cells. Additional
experiments revealed that <b>5f</b> inhibited the enzymatic
activity of multiple kinases, including AURKA, FLT3, GSK3A, MAP3K,
MEK, RSK2, RSK4, PLK4, ULK1, and JAK1. Computational studies showed
that <b>5f</b> can be properly accommodated in the colchicine
binding site of tubulin as well as in the ATP binding clefts of all
examined kinases. Our data indicate that the excellent antiproliferative
profile of <b>5f</b> may be derived from its interactions with
multiple cellular targets
12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents
The synthesis and biological evaluation
of a series of 12,13-aziridinyl
epothilone B analogues is described. These compounds were accessed
by a practical, general process that involved a 12,13-olefinic methyl
ketone as a starting material obtained by ozonolytic cleavage of epothilone
B followed by tungsten-induced deoxygenation of the epoxide moiety.
The attachment of the aziridine structural motif was achieved by application
of the Ess–Kürti–Falck aziridination, while the
heterocyclic side chains were introduced via stereoselective phosphonate-based
olefinations. In order to ensure high (<i>E</i>) selectivities
for the latter reaction for electron-rich heterocycles, it became
necessary to develop and apply an unprecedented modification of the
venerable Horner–Wadsworth–Emmons reaction, employing
2-fluoroethoxyphosphonates that may prove to be of general value in
organic synthesis. These studies resulted in the discovery of some
of the most potent epothilones reported to date. Equipped with functional
groups to accommodate modern drug delivery technologies, some of these
compounds exhibited picomolar potencies that qualify them as payloads
for antibody drug conjugates (ADCs), while a number of them revealed
impressive activities against drug resistant human cancer cells, making
them desirable for potential medical applications
12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents
The synthesis and biological evaluation
of a series of 12,13-aziridinyl
epothilone B analogues is described. These compounds were accessed
by a practical, general process that involved a 12,13-olefinic methyl
ketone as a starting material obtained by ozonolytic cleavage of epothilone
B followed by tungsten-induced deoxygenation of the epoxide moiety.
The attachment of the aziridine structural motif was achieved by application
of the Ess–Kürti–Falck aziridination, while the
heterocyclic side chains were introduced via stereoselective phosphonate-based
olefinations. In order to ensure high (<i>E</i>) selectivities
for the latter reaction for electron-rich heterocycles, it became
necessary to develop and apply an unprecedented modification of the
venerable Horner–Wadsworth–Emmons reaction, employing
2-fluoroethoxyphosphonates that may prove to be of general value in
organic synthesis. These studies resulted in the discovery of some
of the most potent epothilones reported to date. Equipped with functional
groups to accommodate modern drug delivery technologies, some of these
compounds exhibited picomolar potencies that qualify them as payloads
for antibody drug conjugates (ADCs), while a number of them revealed
impressive activities against drug resistant human cancer cells, making
them desirable for potential medical applications
Design, Synthesis, and Preclinical Evaluation of 4‑Substituted-5-methyl-furo[2,3‑<i>d</i>]pyrimidines as Microtubule Targeting Agents That Are Effective against Multidrug Resistant Cancer Cells
The design, synthesis, and biological
evaluations of eight 4-substituted
5-methyl-furoÂ[2,3-<i>d</i>]Âpyrimidines are reported. Synthesis
involved <i>N</i><sup>4</sup>-alkylation of <i>N</i>-aryl-5-methylfuroÂ[2,3-<i>d</i>]Âpyrimidin-4-amines, obtained
from Ullmann coupling of 4-amino-5-methylfuroÂ[2,3-<i>d</i>]Âpyrimidine and appropriate aryl iodides. Compounds <b>3</b>, <b>4</b>, and <b>9</b> showed potent microtubule depolymerizing
activities, while compounds <b>6</b>–<b>8</b> had
slightly lower potency. Compounds <b>4</b>, <b>6</b>, <b>7</b>, and <b>9</b> inhibited tubulin assembly with IC<sub>50</sub> values comparable to that of combretastatin A-4 (CA-4).
Compounds <b>3</b>, <b>4</b>, and <b>6</b>–<b>9</b> circumvented Pgp and βIII-tubulin mediated drug resistance,
mechanisms that can limit the efficacy of paclitaxel, docetaxel, and
the vinca alkaloids. In the NCI 60-cell line panel, compound <b>3</b> exhibited GI<sub>50</sub> values less than 10 nM in 47 of
the cell lines. In an MDA-MB-435 xenograft model, compound <b>3</b> had statistically significant antitumor effects. The biological
effects of <b>3</b> identify it as a novel, potent microtubule
depolymerizing agent with antitumor activity
Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors
Structure–activity relationship translation offers
an expeditious
means for discovery of new active series. This approach was applied
to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule
disruptors. The two A-ring elements of a three-point steroidal pharmacophore
were incorporated into a THIQ-based A,B-ring mimic to which an H-bond
acceptor was attached as the third motif. Optimization of the representative<b> 6c</b> through conformational biasing delivered
a 10-fold gain in activity and a new series of microtubule disruptors
(e.g., <b>9c</b>) with antiproliferative activity in the nanomolar
range. The THIQ derivatives match, or surpass, the activities of the
steroidal series and exhibit improved physicochemical properties
Discovery of Antitubulin Agents with Antiangiogenic Activity as Single Entities with Multitarget Chemotherapy Potential
Antiangiogenic
agents (AA) are cytostatic, and their utility in
cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic
agents. Clinical combinations of vascular endothelial growth factor
receptor-2 (VEGFR2) inhibitors with antitubulin agents have been particularly
successful. We have discovered a novel, potentially important analogue,
that combines potent VEGFR2 inhibitory activity (comparable to that
of sunitinib) with potent antitubulin activity (comparable to that
of combretastatin A-4 (CA)) in a single molecule, with GI<sub>50</sub> values of 10<sup>–7</sup> M across the entire NCI 60 tumor
cell panel. It potently inhibited tubulin assembly and circumvented
the most clinically relevant tumor resistance mechanisms (P-glycoprotein
and β-III tubulin expression) to antimicrotubule agents. The
compound is freely water-soluble as its HCl salt and afforded excellent
antitumor activity <i>in vivo</i>, superior to docetaxel,
sunitinib, or Temozolomide, without any toxicity