5 research outputs found
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
Design, Synthesis, and Structure–Activity Relationships of Azolylmethylpyrroloquinolines as Nonsteroidal Aromatase Inhibitors
A small library of both [2,3-<i>h</i>] and [3,2-<i>f</i>] novel pyrroloquinolines
equipped with an azolylmethyl
group was designed and synthesized as nonsteroidal CYP19 aromatase
inhibitors. The results showed that azolylmethyl derivatives <b>11</b>, <b>13</b>, <b>14</b>, <b>21</b>, and <b>22</b> exhibited an inhibitory potency on aromatase comparable
to that of letrozole chosen as a reference compound. When assayed
on CYP11B1 (steroid-11β-hydroxylase) and CYP17 (17α-hydroxy/17,20-lyase),
compound <b>22</b> was found to be the best and most selective
CYP19 inhibitor of them all. In a panel of nine human cancer cell
lines, all compounds were either slightly cytotoxic or not at all.
Docking simulations were carried out to inspect crucial enzyme/inhibitor
interactions such as hydrophobic interactions, hydrogen bonding, and
heme iron coordination. This study, along with the prediction of the
pharmacokinetics of compounds <b>11</b>, <b>13</b>, <b>14</b>, <b>21</b>, and <b>22</b>, demonstrates that
the pyrroloquinoline scaffold represents a starting point for the
development of new pyrroloquinoline-based aromatase inhibitors
Synthesis and Biological Evaluation of 2‑(Alkoxycarbonyl)-3-Anilinobenzo[<i>b</i>]thiophenes and Thieno[2,3‑<i>b</i>]pyridines as New Potent Anticancer Agents
Two new series of
inhibitors of tubulin polymerization based on
the 2-(alkoxycarbonyl)-3-(3′,4′,5′-trimethoxyanilino)ÂbenzoÂ[<i>b</i>]Âthiophene and thienoÂ[2,3-<i>b</i>]Âpyridine molecular
skeletons were synthesized and evaluated for antiproliferative activity
on a panel of cancer cell lines, inhibition of tubulin polymerization,
cell cycle effects, and in vivo potency. Antiproliferative activity
was strongly dependent on the position of the methyl group on the
benzene portion of the benzoÂ[<i>b</i>]Âthiophene nucleus,
with the greatest activity observed when the methyl was located at
the C-6 position. Also, in the smaller thienoÂ[2,3-<i>b</i>]Âpyridine series, the introduction of the methyl group at the C-6
position resulted in improvement of antiproliferative activity to
the nanomolar level. The most active compounds (<b>4i</b> and <b>4n</b>) did not induce cell death in normal human lymphocytes,
suggesting that the compounds may be selective against cancer cells.
Compound <b>4i</b> significantly inhibited in vivo the growth
of a syngeneic hepatocellular carcinoma in Balb/c mice
Synthesis, Antimitotic and Antivascular Activity of 1‑(3′,4′,5′-Trimethoxybenzoyl)-3-arylamino-5-amino-1,2,4-triazoles
A new
class of compounds that incorporated the structural motif
of the 1-(3′,4′,5′-trimethoxtbenzoyl)-3-arylamino-5-amino-1,2,4-triazole
molecular skeleton was synthesized and evaluated for their antiproliferative
activity in vitro, interactions with tubulin, and cell cycle effects.
The most active agent, <b>3c</b>, was evaluated for antitumor
activity in vivo. Structure–activity relationships were elucidated
with various substituents on the phenyl ring of the anilino moiety
at the C-3 position of the 1,2,4-triazole ring. The best results for
inhibition of cancer cell growth were obtained with the <i>p</i>-Me, <i>m</i>,<i>p</i>-diMe, and <i>p</i>-Et phenyl derivatives <b>3c</b>, <b>3e</b>, and <b>3f</b>, respectively, and overall, these compounds were more or
less as active as CA-4. Their vascular disrupting activity was evaluated
in HUVEC cells, with compound <b>3c</b> showing activity comparable
with that of CA-4. Compound <b>3c</b> almost eliminated the
growth of syngeneic hepatocellular carcinoma in Balb/c mice, suggesting
that <b>3c</b> could be a new antimitotic agent with clinical
potential
Concise Synthesis and Biological Evaluation of 2‑Aroyl-5-Amino Benzo[<i>b</i>]thiophene Derivatives As a Novel Class of Potent Antimitotic Agents
The
biological importance of microtubules make them an interesting target
for the synthesis of antitumor agents. The 2-(3′,4′,5′-trimethoxybenzoyl)-5-aminobenzoÂ[<i>b</i>]Âthiophene moiety was identified as a novel scaffold for
the preparation of potent inhibitors of microtubule polymerization
acting through the colchicine site of tubulin. The position of the
methoxy group on the benzoÂ[<i>b</i>]Âthiophene was important
for maximal antiproliferative activity. Structure–activity
relationship analysis established that the best activities were obtained
with amino and methoxy groups placed at the C-5 and C-7 positions,
respectively. Compounds <b>3c</b>–<b>e</b> showed
more potent inhibition of tubulin polymerization than combretastatin
A-4 and strong binding to the colchicine site. These compounds also
demonstrated substantial antiproliferative activity, with IC<sub>50</sub> values ranging from 2.6 to 18 nM in a variety of cancer cell lines.
Importantly, compound <b>3c</b> (50 mg/kg), significantly inhibited
the growth of the human osteosarcoma MNNG/HOS xenograft in nude mice