Progress in the Chemistry of Cytochalasans
75
109 lung carcinoma and B16 melanoma. In addition, chaetoglobosins A–G (210–
216) and J (217) showed cytotoxicity against HeLa cells with IC 50 values ranging
from 3 to 20 μg/cm
3 [108], while chaetoglobosins A (210), B (211), D (212), J
(217), Q (234), and T (236) as well as prochaetoglobosins I (221) and II (222) [115]
displayed cytotoxicity against the P388 murine leukemia cell line [121]. Phomacins
A–C (413, 414, and 348) from Phoma sp. exhibited inhibitory activities against HT29
colon adenocarcinoma cells, with IC 50 values of 0.6, 1.4, and 7.4 μg/cm
3 , respectively [160]. Cytoglobosins C and D (238 and 239) each displayed inhibitory activity
toward the A-549 cell line (IC 50 2.26 and 2.55 μM) [122].
Recently, many new cytochalasans having cytotoxic activities against cancer cells
have been reported. Amichalasines A (458) and B (459), which represent a new type
of cytochalasan heterotrimer, were isolated from Aspergillus micronesiensis PG1, and their IC 50 values determined against HL60 cells were 1.71 and 3.74 μM,
respectively [195]. Asperflavipine A (468), a structurally complex merocytochalasan isolated from Aspergillus flavipes, was found to possess moderate cytotoxicity
against seven cancer cell lines (MDA-MB-231, RKO, Hep-3B, HCT116, Jurkat,
NB4 and HL60), with IC 50 values ranging from 12.7 to 27.6 μM [209]. Cytochathiazine B (338), which represents a new type of merocytochalasan isolated by the
coculturing of Chaetomium globosum and Aspergillus flavipes, showed moderate
antiproliferative activities against NB4 and HL-60 cells, with IC 50 values of 9.6 and
12.5 μM, respectively [154]. Flavichalasines N (424) and O (433), also isolated from
Aspergillus flavipes PJ03-11, exhibited cytotoxic activities against three cancer cell
lines (THP1, HL-60, and PC3), having IC 50 values ranging from 3.0 to 15.1 μM
[187]. Similarly, cytoglobosins H (255) and I (256) showed antiproliferative effects
for the LNCaP and B16F10 cell lines [126].
As the cytoskeletal structure acts at a specific time point in the cell cycle, the induction of cell cycle arrest at a specific checkpoint, and thereby inducing apoptosis, is a
common mechanism for the cytotoxic effects of established anticancer drugs, as well
as cytochalasans. Mechanically, cytochalasans initially alter the dynamic properties
of microfilaments and inhibit cytokinesis of the cell without an effect on nuclear
division; after this, normal cells enter the G0 resting state until sufficient actin levels
have been attained for successful cytokinesis, while the fast-growing cancer cells
typically continue to progress through the cell cycle, resulting in the formation of
enlarged, multinucleated cells. A multinucleation phenomenon is observed almost
exclusively in cancer cells, potentially representing a cancer-targeting attribute of
cytochalasans [207]. It has been reported that many cytochalasins arrest the cell
cycle and then induce apoptosis cell death. Treatment with cytochalasin D (2) led
to arrest of the G1-to-S transition and induced apoptosis in cells retaining wild-type
p53, while cells with inactivated p53 showed a partial rescue effect [210]. Cytochalasin B (110) induced G2/M phase cell cycle arrest, and activated ROS signaling
and the Ca
2+ -associated mitochondrial apoptotic pathways, using ZR-75-1 human
breast cancer cells [211]. Chaetoglobosin A (210) showed preferential induction
of apoptosis in chronic lymphocytic leukemia cells through targeting filamentous
actin, and it thereby induces G2/M cell-cycle arrest [212]. Chaetoglobosin K (273)
has been shown to inhibit cytokinesis, promote apoptosis, as well as to prevent
75
109 lung carcinoma and B16 melanoma. In addition, chaetoglobosins A–G (210–
216) and J (217) showed cytotoxicity against HeLa cells with IC 50 values ranging
from 3 to 20 μg/cm
3 [108], while chaetoglobosins A (210), B (211), D (212), J
(217), Q (234), and T (236) as well as prochaetoglobosins I (221) and II (222) [115]
displayed cytotoxicity against the P388 murine leukemia cell line [121]. Phomacins
A–C (413, 414, and 348) from Phoma sp. exhibited inhibitory activities against HT29
colon adenocarcinoma cells, with IC 50 values of 0.6, 1.4, and 7.4 μg/cm
3 , respectively [160]. Cytoglobosins C and D (238 and 239) each displayed inhibitory activity
toward the A-549 cell line (IC 50 2.26 and 2.55 μM) [122].
Recently, many new cytochalasans having cytotoxic activities against cancer cells
have been reported. Amichalasines A (458) and B (459), which represent a new type
of cytochalasan heterotrimer, were isolated from Aspergillus micronesiensis PG1, and their IC 50 values determined against HL60 cells were 1.71 and 3.74 μM,
respectively [195]. Asperflavipine A (468), a structurally complex merocytochalasan isolated from Aspergillus flavipes, was found to possess moderate cytotoxicity
against seven cancer cell lines (MDA-MB-231, RKO, Hep-3B, HCT116, Jurkat,
NB4 and HL60), with IC 50 values ranging from 12.7 to 27.6 μM [209]. Cytochathiazine B (338), which represents a new type of merocytochalasan isolated by the
coculturing of Chaetomium globosum and Aspergillus flavipes, showed moderate
antiproliferative activities against NB4 and HL-60 cells, with IC 50 values of 9.6 and
12.5 μM, respectively [154]. Flavichalasines N (424) and O (433), also isolated from
Aspergillus flavipes PJ03-11, exhibited cytotoxic activities against three cancer cell
lines (THP1, HL-60, and PC3), having IC 50 values ranging from 3.0 to 15.1 μM
[187]. Similarly, cytoglobosins H (255) and I (256) showed antiproliferative effects
for the LNCaP and B16F10 cell lines [126].
As the cytoskeletal structure acts at a specific time point in the cell cycle, the induction of cell cycle arrest at a specific checkpoint, and thereby inducing apoptosis, is a
common mechanism for the cytotoxic effects of established anticancer drugs, as well
as cytochalasans. Mechanically, cytochalasans initially alter the dynamic properties
of microfilaments and inhibit cytokinesis of the cell without an effect on nuclear
division; after this, normal cells enter the G0 resting state until sufficient actin levels
have been attained for successful cytokinesis, while the fast-growing cancer cells
typically continue to progress through the cell cycle, resulting in the formation of
enlarged, multinucleated cells. A multinucleation phenomenon is observed almost
exclusively in cancer cells, potentially representing a cancer-targeting attribute of
cytochalasans [207]. It has been reported that many cytochalasins arrest the cell
cycle and then induce apoptosis cell death. Treatment with cytochalasin D (2) led
to arrest of the G1-to-S transition and induced apoptosis in cells retaining wild-type
p53, while cells with inactivated p53 showed a partial rescue effect [210]. Cytochalasin B (110) induced G2/M phase cell cycle arrest, and activated ROS signaling
and the Ca
2+ -associated mitochondrial apoptotic pathways, using ZR-75-1 human
breast cancer cells [211]. Chaetoglobosin A (210) showed preferential induction
of apoptosis in chronic lymphocytic leukemia cells through targeting filamentous
actin, and it thereby induces G2/M cell-cycle arrest [212]. Chaetoglobosin K (273)
has been shown to inhibit cytokinesis, promote apoptosis, as well as to prevent