98
H. Zhu et al.
5 Chemical Syntheses of Cytochalasans
The typical structures of cytochalasans feature a highly substituted perhydroisoindolone moiety fused by a macrocyclic ring—either a carbocycle (periconiasin G
(412) and periconiasin A (404)), a lactone (cytochalasin B (110)) or a cyclic carbonate
(phenochalasin A (202)), as shown in Fig. 22A. The macrocycles presented in these
structures are normally 11- to 14-membered rings. Periconiasin G (412), bearing a
unique 5/6/7-fused ring system, is the smallest member among the cytochalasans
[15]. In 2013, cytochalasans bearing a medium-sized ring were identified by Dai
and associates, as represented by periconiasin A (404) from the endophytic fungus
Periconia sp. [182]. This constituted a new subclass of cytochalasans, featuring
an unprecedented 5/6/9 tricyclic framework. In addition, several structurally relevant congeners were also reported by the same laboratory in 2015, as represented
by periconiasins D–F (408–410, Fig. 22B) [184]. Differing from previously identified cytochalasans, periconiasins D–F (408–410) possess highly complex polycyclic
architectures containing multiple chiral carbon centers. Aspergillin PZ (398) also has
a polycyclic architecture and its intricate pentacyclic skeleton features one quaternary carbon and ten contiguous stereocenters, of which five reside on an oxabicyclo[3.2.1]octane subunit [176]. In 2015, Zhang and coworkers isolated and determined a series of novel cytochalasans represented by asperchalasines A–D (455
and 448–450) from a culture broth of Aspergillus flavipes, which was formed by
a Diels–Alder reaction between aspochalasin B (344) and epicoccine (Fig. 22C)
[193]. Moreover, asperchalasine A (455), the first cytochalasan heterotrimer, features
a unique decacyclic 5/6/11/5/5/6/5/11/6/5 ring system consisting of as many as 20
chiral centers. It was the first example of a dimeric cytochalasan alkaloid and later
classified as a “merocytochalasan” (Fig. 22C). From this point on, a series of merocytochalasans was discovered by the same group, as exemplified by epicochalasines A
(461) and B (462) and asperflavipine A (468), with high degrees of functionalization
and intricate polycyclic structures, which greatly enriched the chemical diversity of
the cytochalasan family [4, 196]. Equally noteworthy is the fact that asperchalasine
A (455) induced significant G1-phase cell cycle arrest by selectively inhibiting cyclin
A, CDK2, and CDK6 in cancerous, but not normal cells. On the other hand, epicochalasines A (461) and B (462) induced significant G2/M-phase cell-cycle arrest and
apoptosis in leukemia cells through the activation of caspase-3 and the degradation
of PARP, thus potentially representing excellent lead compounds for antineoplastic
drug development.
The complex and densely functionalized structures of cytochalasans combined
with their promising biological profiles render them attractive synthetic targets and
considerable efforts in the past have been devoted to the total synthesis of cytochalasans. As shown in Fig. 22, the most representative structure of a cytochalasan is a
tricyclic hydroisoindolone moiety fused by a macrocyclic ring. Cytochalasans with
more complex structures, such as periconiasins D–E (408–410), aspergillin PZ (398)
and the merocytochalasans, as shown in Fig. 22B and 22C, can be furnished from
their related tricyclic precursor through biomimetic synthesis pathways. Therefore,
H. Zhu et al.
5 Chemical Syntheses of Cytochalasans
The typical structures of cytochalasans feature a highly substituted perhydroisoindolone moiety fused by a macrocyclic ring—either a carbocycle (periconiasin G
(412) and periconiasin A (404)), a lactone (cytochalasin B (110)) or a cyclic carbonate
(phenochalasin A (202)), as shown in Fig. 22A. The macrocycles presented in these
structures are normally 11- to 14-membered rings. Periconiasin G (412), bearing a
unique 5/6/7-fused ring system, is the smallest member among the cytochalasans
[15]. In 2013, cytochalasans bearing a medium-sized ring were identified by Dai
and associates, as represented by periconiasin A (404) from the endophytic fungus
Periconia sp. [182]. This constituted a new subclass of cytochalasans, featuring
an unprecedented 5/6/9 tricyclic framework. In addition, several structurally relevant congeners were also reported by the same laboratory in 2015, as represented
by periconiasins D–F (408–410, Fig. 22B) [184]. Differing from previously identified cytochalasans, periconiasins D–F (408–410) possess highly complex polycyclic
architectures containing multiple chiral carbon centers. Aspergillin PZ (398) also has
a polycyclic architecture and its intricate pentacyclic skeleton features one quaternary carbon and ten contiguous stereocenters, of which five reside on an oxabicyclo[3.2.1]octane subunit [176]. In 2015, Zhang and coworkers isolated and determined a series of novel cytochalasans represented by asperchalasines A–D (455
and 448–450) from a culture broth of Aspergillus flavipes, which was formed by
a Diels–Alder reaction between aspochalasin B (344) and epicoccine (Fig. 22C)
[193]. Moreover, asperchalasine A (455), the first cytochalasan heterotrimer, features
a unique decacyclic 5/6/11/5/5/6/5/11/6/5 ring system consisting of as many as 20
chiral centers. It was the first example of a dimeric cytochalasan alkaloid and later
classified as a “merocytochalasan” (Fig. 22C). From this point on, a series of merocytochalasans was discovered by the same group, as exemplified by epicochalasines A
(461) and B (462) and asperflavipine A (468), with high degrees of functionalization
and intricate polycyclic structures, which greatly enriched the chemical diversity of
the cytochalasan family [4, 196]. Equally noteworthy is the fact that asperchalasine
A (455) induced significant G1-phase cell cycle arrest by selectively inhibiting cyclin
A, CDK2, and CDK6 in cancerous, but not normal cells. On the other hand, epicochalasines A (461) and B (462) induced significant G2/M-phase cell-cycle arrest and
apoptosis in leukemia cells through the activation of caspase-3 and the degradation
of PARP, thus potentially representing excellent lead compounds for antineoplastic
drug development.
The complex and densely functionalized structures of cytochalasans combined
with their promising biological profiles render them attractive synthetic targets and
considerable efforts in the past have been devoted to the total synthesis of cytochalasans. As shown in Fig. 22, the most representative structure of a cytochalasan is a
tricyclic hydroisoindolone moiety fused by a macrocyclic ring. Cytochalasans with
more complex structures, such as periconiasins D–E (408–410), aspergillin PZ (398)
and the merocytochalasans, as shown in Fig. 22B and 22C, can be furnished from
their related tricyclic precursor through biomimetic synthesis pathways. Therefore,