4 research outputs found
Higginsianins A and B, Two Diterpenoid α‑Pyrones Produced by <i>Colletotrichum higginsianum</i>, with <i>in Vitro</i> Cytostatic Activity
Two new diterpenoid α-pyrones,
named higginsianins A (<b>1</b>) and B (<b>2</b>), were
isolated from the mycelium
of the fungus <i>Colletotrichum higginsianum</i> grown in
liquid culture. They were characterized as 3-[5a,9b-dimethyl-7-methylene-2-(2-methylpropenyl)dodecahydronaphtho[2,1-<i>b</i>]furan-6-ylmethyl]-4-hydroxy-5,6-dimethylpyran-2-one and
4-hydroxy-3-[6-hydroxy-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-enyl)decahydronaphthalen-1-ylmethyl]-5,6-dimethylpyran-2-one,
respectively, by using NMR, HRESIMS, and chemical methods. The structure
and relative configuration of higginsianin A (<b>1</b>) were
confirmed by X-ray diffractometric analysis, while its absolute configuration
was assigned by electronic circular dichroism (ECD) experiments and
calculations using a solid-state ECD/TDDFT method. The relative and
absolute configuration of higginsianin B (<b>2</b>), which did
not afford crystals suitable for X-ray analysis, were determined by
NMR analysis and by ECD in comparison with higginsianin A. <b>1</b> and <b>2</b> were the C-8 epimers of subglutinol A and diterpenoid
BR-050, respectively. The evaluation of <b>1</b> and <b>2</b> for antiproliferative activity against a panel of six cancer cell
lines revealed that the IC<sub>50</sub> values, obtained with cells
reported to be sensitive to pro-apoptotic stimuli, are by more than
1 order of magnitude lower than their apoptosis-resistant counterparts
(1 vs >80 μM). Finally, three hemisynthetic derivatives of <b>1</b> were prepared and evaluated for antiproliferative activity.
Two of these possessed IC<sub>50</sub> values and differential sensitivity
profiles similar to those of <b>1</b>
Higginsianins A and B, Two Diterpenoid α‑Pyrones Produced by <i>Colletotrichum higginsianum</i>, with <i>in Vitro</i> Cytostatic Activity
Two new diterpenoid α-pyrones,
named higginsianins A (<b>1</b>) and B (<b>2</b>), were
isolated from the mycelium
of the fungus <i>Colletotrichum higginsianum</i> grown in
liquid culture. They were characterized as 3-[5a,9b-dimethyl-7-methylene-2-(2-methylpropenyl)dodecahydronaphtho[2,1-<i>b</i>]furan-6-ylmethyl]-4-hydroxy-5,6-dimethylpyran-2-one and
4-hydroxy-3-[6-hydroxy-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-enyl)decahydronaphthalen-1-ylmethyl]-5,6-dimethylpyran-2-one,
respectively, by using NMR, HRESIMS, and chemical methods. The structure
and relative configuration of higginsianin A (<b>1</b>) were
confirmed by X-ray diffractometric analysis, while its absolute configuration
was assigned by electronic circular dichroism (ECD) experiments and
calculations using a solid-state ECD/TDDFT method. The relative and
absolute configuration of higginsianin B (<b>2</b>), which did
not afford crystals suitable for X-ray analysis, were determined by
NMR analysis and by ECD in comparison with higginsianin A. <b>1</b> and <b>2</b> were the C-8 epimers of subglutinol A and diterpenoid
BR-050, respectively. The evaluation of <b>1</b> and <b>2</b> for antiproliferative activity against a panel of six cancer cell
lines revealed that the IC<sub>50</sub> values, obtained with cells
reported to be sensitive to pro-apoptotic stimuli, are by more than
1 order of magnitude lower than their apoptosis-resistant counterparts
(1 vs >80 μM). Finally, three hemisynthetic derivatives of <b>1</b> were prepared and evaluated for antiproliferative activity.
Two of these possessed IC<sub>50</sub> values and differential sensitivity
profiles similar to those of <b>1</b>
Novel Microtubule-Targeting 7‑Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities
Docking studies of tubulin-targeting
C2-substituted 7-deazahypoxanthine
analogues of marine alkaloid rigidins led to the design and synthesis
of compounds containing linear C2-substituents. The C2-alkynyl analogue
was found to have double- to single-digit nanomolar antiproliferative
IC<sub>50</sub> values and showed statistically significant tumor
size reduction in a colon cancer mouse model at nontoxic concentrations.
These results provide impetus and further guidance for the development
of these rigidin analogues as anticancer agents
Exploring Natural Product Chemistry and Biology with Multicomponent Reactions. 5. Discovery of a Novel Tubulin-Targeting Scaffold Derived from the Rigidin Family of Marine Alkaloids
We
developed synthetic chemistry to access the marine alkaloid
rigidins and over 40 synthetic analogues based on the 7-deazaxanthine,
7-deazaadenine, 7-deazapurine, and 7-deazahypoxanthine skeletons.
Analogues based on the 7-deazahypoxanthine skeleton exhibited nanomolar
potencies against cell lines representing cancers with dismal prognoses,
tumor metastases, and multidrug resistant cells. Studies aimed at
elucidating the mode(s) of action of the 7-deazahypoxanthines in cancer
cells revealed that they inhibited in vitro tubulin polymerization
and disorganized microtubules in live HeLa cells. Experiments evaluating
the effects of the 7-deazahypoxanthines on the binding of [<sup>3</sup>H]colchicine to tubulin identified the colchicine site on tubulin
as the most likely target for these compounds in cancer cells. Because
many microtubule-targeting compounds are successfully used to fight
cancer in the clinic, we believe the new chemical class of antitubulin
agents represented by the 7-deazahypoxanthine rigidin analogues have
significant potential as new anticancer agents