Review pubs.acs.org/CR
Organic Carbonates from Natural Sources Hua Zhang, Hong-Bing Liu, and Jian-Min Yue* State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China Acknowledgments Abbreviations Chemistry Biology References
1. INTRODUCTION Organic carbonates (OCs), also known as carbonic acid esters, are a class of compounds with a carbonyl flanked by two alkoxy/aryloxy groups. Their structures are represented by the formula R1OCOOR2 where R1 and R1 can be the same or different alkyl/aryl groups or form a cyclic architecture. OCs are playing more and more important roles in our modern life with rapidly increasing applications in both industry (e.g., plastic materials and fuel additives) and scientific laboratories (e.g., solvents and synthetic blocks), a fact which has been wellsummarized in several excellent reviews.1−4 While OCs from synthetic approaches have been wellstudied because of their utilization in numerous fields, natural OCs have been somewhat overlooked. During our study of chuktabrin A (2),5 we noticed that there was often confusion and ambiguity regarding the natural occurrence of OCs. For instance, even 30 years after the discovery of aldgamycin E (27), which is likely the earliest natural OC with a recorded structure,6 soyasapogenol G (1) was still claimed to be the first example in 1996.7 Another example is hololeucin (14), which was reported to be the first natural terpenoid carbonate in 20068 even with the powerful searching tools such as SciFinder and Reaxys available at that time (both possessing a structurebased searching option), whereas a similar sesquiterpenoid analogue, 13, had already been isolated in 1994.9 A very important reason for the above misclaims could be the fact that research articles of natural OCs are often buried in countless reports of synthetic OCs, which makes it a very challenging and time-consuming task to dig them out. In addition, another reason might lie in the nomenclature used by scientists in different research areas at different periods. Apart from the widely accepted terminology “organic carbonate”, “carbonic acid ester” was preferred by early chemists (before ca. 1960), while a number of organic chemists used the systematic nomenclature “1,3-dioxo-2-one” to describe the carbonate group and a few researchers employed the name “organocarbonate”. While an increasing number of reports on natural OCs has emerged especially in the new century, a literature review by us revealed that there have been no documents summarizing the knowledge about this unusual class of natural products.
CONTENTS 1. Introduction 2. Organic Carbonates from Plants 2.1. Terpenoid Carbonates 2.2. Alkaloidal Carbonates 2.3. Phenolic Carbonates 2.4. Miscellaneous 3. Organic Carbonates from Microbes 3.1. Organic Carbonates from Bacteria 3.1.1. Non-Macrocyclic Carbonates 3.1.2. Macrocyclic Carbonates (Aldgamycin Carbonates) 3.2. Organic Carbonates from Fungi 3.2.1. Non-Macrocyclic Carbonates 3.2.2. Macrocyclic Carbonates (Cytochalasin Carbonates) 3.3. Unconfirmed Organic Carbonates 4. Physicochemical Properties 4.1. IR Data 4.2. NMR Data 4.3. Stability 5. Reactions and Syntheses 5.1. Reactions and Syntheses of Natural Organic Carbonates 5.2. Syntheses of Non-Natural Organic Carbonates 6. Biogenesis of Carbonate Functionalities 7. Biological Properties 7.1. Biological Properties of Phytogenous Carbonates 7.2. Biological Properties of Bacterial Carbonates 7.3. Biological Properties of Fungal Carbonates 7.4. Biological Properties of Cytochalasin E (39) 7.4.1. Effects of Cytochalasin E (39) on Plants 7.4.2. Effects of Cytochalasin E (39) on Animals 8. Conclusions Author Information Corresponding Author Notes Biographies © XXXX American Chemical Society
N N N N N
A B B C E E E E E E F F F G G G G G G G H J J K K L L L L M M M M M
Received: November 1, 2012
A
dx.doi.org/10.1021/cr300430e | Chem. Rev. XXXX, XXX, XXX−XXX
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Table 1. Organic Carbonates from Plants compound
source
extraction
1 2
soyasapogenol G chuktabrin A
1738 1815
148.5a 152.4a
Melilotus messanensis7 Chukrasia tabularis5
− twigs, leaves
water 95% EtOH
3
chuktabrin C
1819
152.3a
C. tabularis var. velutina10
stem bark
95% EtOH
4
chuktabrin D
1796
153.0a
C. tabularis var. velutina10
stem bark
95% EtOH
5
chuktabrin E
1816
152.4a
C. tabularis var. velutina10
stem bark
95% EtOH
6
chuktabrin F
1816
151.9a
C. tabularis var. velutina10
stem bark
95% EtOH
7
chuktabrin G
1819
151.0b
C. tabularis var. velutina10
stem bark
95% EtOH
8
chuktabrin H
1797
151.9a
C. tabularis var. velutina10
stem bark
95% EtOH
9
chuktabrin I
1807
152.1a
C. tabularis var. velutina10
stem bark
95% EtOH
10
chuktabrin J
1810
150.8b
C. tabularis var. velutina10
stem bark
95% EtOH
b
11
11 12
chuktabrin K chukvelutin D
1800 1804
152.0 152.3b
C. tabularis var. velutina C. tabularis var. velutina12
stem bark stem bark
95% EtOH 95% EtOH
13
−
1738g
173.0a,g
Fabiana imbricata9
aerial parts
petrol
14 15 16
hololeucin genkwanin I paxiphylline C
1782h − 1745
155.4d 156.6c 155.6a
aerial parts flower bud twigs, leaves
acetone 95% EtOH 95% EtOH
17 18
alstolucine A rhamnakoside A
1742 1703g
155.0a 143.2e,g
Centaurea hololeuca8 Daphne genkwa13 Daphniphyllium paxianum14 Alstonia spatulata15 Rhamnus nakaharai17
leaves wood
95% EtOH MeOH
19
rhamnakoside B
1708g
155.0e
R. nakaharai17
wood
MeOH
20 21
− cycloolivil carbonate −
1750/1747 1820, 1785
153.4e 156.0f
Cleidion brevipetiolatum19 Strychnos guianensis16
whole plant root
155.2a
Calotropis procera20
leaves
22 a
13 C (ppm)
IR (cm−1)
trivial name
b
− c
d
e
f
collection site Trebujena, Cádiz, Spain Xishuangbanna, Yunnan, China Xishuangbanna, Yunnan, China Xishuangbanna, Yunnan, China Xishuangbanna, Yunnan, China Xishuangbanna, Yunnan, China Xishuangbanna, Yunnan, China Xishuangbanna, Yunnan, China Xishuangbanna, Yunnan, China Xishuangbanna, Yunnan, China as above Xishuangbanna, Yunnan, China Cajon del Maipo, Central Chile Hermon, Lebanon Mianyang, Sichuan, China Sichuan, China
yield (%) 0.00122 0.00016 0.00004 0.00009 10 mg/kg by i.v. and i.p. injection, respectively.31 Further investigations by Ishida and Ohtsuki established that 26 not only inhibits DNA synthesis in sensitive cells but also induces
Table 6. Antibacterial Activities (MIC, μg/mL) of 27−29
a
K
bacterial strain
27
28
29
Staphylococcus aureus FDA209P S. aureus Smitha S. aureus MS353 Streptococcus pyogenes 1099a S. pyogenes DP type 2a Bacillus subtilis ATCC663336 B. subtilis IAM1729 Micrococcus luteus ATCC9341 Salmonella typhimurium IID971 M. luteus IFC12708 B. subtilis ATCC663337 Proteus vulgaris ATCC3851 S. typhimurium ATCC14028
− − − − − − − − − 0.78 25.00 >50 1.56
1.56 3.12 6.25 12.5 >100 6.25 0.39 0.39 >100 1.56 50.00 >50 1.56
1.56 0.39 1.56 1.56 100 1.56 0.1 0.2 >100 0.78 12.50 12.50 1.56
Clinically isolated strains. dx.doi.org/10.1021/cr300430e | Chem. Rev. XXXX, XXX, XXX−XXX
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hermonthica by 63% at 10−4 M.105 In addition, 39 has a direct effect on photosynthesis in young leaves of Malus domestica (apple), possibly resulting from the impairment of light harvesting,106 and the production of 39 was shown to be related to the pathogenicity of R. necatrix to apple trees infected with white root rot.54 Loake and colleagues further reported that treatment of wild-type Arabidopsis plants with 39 causes a decrease in nonhost resistance by which plant immunity against the majority of the microbial pathogens was conveyed,107 while Foissner and Wasteneys108 investigated the effects of 39 in an ideal experimental system on the giant internodal cell motility of the characean alga Nitella pseudoflabellata. 7.4.2. Effects of Cytochalasin E (39) on Animals. 7.4.2.1. In Vivo Bioactivities. The earliest in vivo experiments on the toxicity of 39 toward animals were performed by Büchi et al., which showed that 39 has acute toxicity toward mammals and kills rats within a few hours after dosing (LD50 = 2.6 and 9.1 mg/kg for i.p. and oral administration, respectively).51 The death was believed to be caused by circulatory collapse arising from massive extravascular effusion of plasma. Additionally, further toxicity and/or teratogenicity studies of 39 on mice,109 guinea pigs,109 embryonic chicks,59 and brine shrimps104 have been reported, and 39 was also found to inhibit both the growth of Lewis lung tumors by around 72% and the angiogenesis induced by basic fibroblast growth factor by 40−50% in the mouse cornea assay.110 7.4.2.2. In Vitro Bioactivities. In vitro bioassays have played an overwhelming role in the studies of pharmacological functions of 39 because of their enormous advantages compared with in vivo experiments. Organic and tissue-level experiments were employed in the investigations of the effects of 39 on some metabolic processes. Following the first report of the inhibition of intestinal glucose absorption in several animal species by 39,111 the inhibitory effects of 39 on glucose absorption in various intestine segments of mice of different ages and sexes were also described,112 whereas 39 seemed to stimulate absorption of fructose derived from sucrose digestion in mouse jejunum.113 Moreover, 39 was also discovered to inhibit galactose114 and Na+-dependent phenylalanine115 absorption in the everted sacs of mouse jejunum as well as water and Na+ absorption in rat ileum.116 As for its direct toxic effects on cells, 39 displayed excellent cytotoxicity against the human tumor cell lines P-388, A-549,69 A2780S (ovary), SW-620 (colon), and HCT-116 (colon) (Table 7)67 and was also found to exhibit decent antiproliferative and cytotoxic effects on human prostate carcinoma cells PC-3 [50% growth inhibition concentration (GI50) = 61 ± 20 nM]117 as well as prostate xenograft tumor cells CWR22, CWR22R, and CWR91 (Table 7).118 Other biological activities include the inhibition of cell reaggregation of the red sponge Microciona prolifera,119 Ehrlich ascites tumore cell adhesion to glass and plastic surfaces,120 Trichomonas vaginalis adhesion to plastic surfaces,121 and HL-60 cell adhesion to CHO-ICAM-1 cells (ovary).68 Another type of important effect of 39 on cells is the induction of superoxide anion (O2−) release. Generation of O2− in guinea pig and human polymorphonuclear leukocytes by treatment with 39 was investigated by Nakagawara and colleagues in 1975122 and 1976,123 respectively, while similar effects on O2− production in human monocytes124,125 and macrophages126 were also observed. In addition, 39 also stimulates rat Kupffer cells,127 human neutrophils,128 and eosinophils and neutrophils of guinea pigs to release O2−.129
S. typhimurium IID 971,36 all three compounds significantly inhibit the growth of the ATCC14028 strain of the same species as shown in Kwon’s report (Table 6).37 7.3. Biological Properties of Fungal Carbonates
Most non-macrocylic OCs from fungi were not found to exhibit interesting bioactivities, although chrysoqueen (34) was recorded as a modest antibacterial agent against Micrococcus luteus IFM 2066 and Bacillus subtilis PCI 219 (MIC values of 33 μg/mL against both).43 In addition, 37 and 38 showed potatomicrotuber-inducing activities only at concentrations up to 1 mM.46,47 Up to the present, the cytochalasin carbonates, particularly cytochalasin E (39), which will be discussed in section 7.4., have the widest range of biological properties and are also the most studied class of compounds among all the natural OCs. Like its analogues without the carbonate moiety,96 compound 40 was also reported to be a toxic agent on its first isolation from nature,58 which was further confirmed by Liu et al.69 on two tumor cell lines, P-388 (leukemia, IC50 = 89 μM) and A549 (lung, IC50 = 8.4 μM), while its effects on cellular structures, cellular events, and actin polymerization (98% capping inhibition and 39% polymerization inhibition) of C3H2K cells (kidney) were also evaluated by a Japanese research group.97 Moreover, its inhibition against angiogenesis was patented in 1998,98 and its effects on mitochondrial biogenesis and function in the treatment of mitochondrial disease were patented 2008.99 Phenochalasins A (42) and B (43) proved to be lipid droplet formation (LDF) inhibitors in mouse peritoneal macrophages in the initial report of Omura’s research team,100 with the former inhibiting LDF in a dose-dependent manner without causing any morphological changes to the macrophages up to 20 μM.101 Further studies also demonstrated that 42 shows very specific inhibition of cholesteryl ester (CE) synthesis (IC50 = 0.61 μM),101,102 while 43 displays better inhibition of both CE and triacylglycerol syntheses (IC50 = 0.23 and 0.38 μM, respectively).101 Moreover, 43 displays strong cytotoxicity against three cancer cell lines, MCF-7 (breast), NCI-H460 (lung), and SF-268 (CNS) (see Table 7), as reported in a very recent Chinese article.75 In addition, scopararane B (45) exhibits moderate antimicrobial activity against Microsporum gypseum SH-MU-4 with a MIC value of 30.3 μM,76 and cytochalasin Z16 (46) and Z19 (48) inhibit the growth of the A549 cell line with IC50 values of 19.5 and 17.4 μM, respectively.65 7.4. Biological Properties of Cytochalasin E (39)
Cytochalasin E (39) is one of the most investigated members of the cytochalasin family because of its wide distribution in nature and variety of biological properties. Since it was initially reported to inhibit thrombocyte aggregation, fibroblast motility, and cytoplasm cleavage in vitro,48 there have been numerous studies regarding its effects on both plants and animals from macroscopic living bodies to microcosmic biomolecules either in vivo or in vitro. 7.4.1. Effects of Cytochalasin E (39) on Plants. Sawai and co-workers first discovered that 39 markedly disturbs the normal metabolic pathway in lettuce seedlings through its inhibition of vascular function and completely inhibits root hair formation even at 1 ppm,103 and a similar inhibitory effect on the growth of tomato seedlings was also observed in Capasso and Randazzo’s report.104 Zonno and Vurro discovered that 39 also inhibits seed germination of the parasitic weed Striga L
dx.doi.org/10.1021/cr300430e | Chem. Rev. XXXX, XXX, XXX−XXX
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Table 7. Cytotoxicity Data (IC50, μM) for 39 and 43 tumor cell line
39
43
P-388 (leukemia) A-549 (lung) A2780S (ovary) SW-620 (colon) HCT-116 (colon) CWR22 (prostate xenograft) CWR22R (prostate xenograft) CWR91 (prostate xenograft) MCF-7 (breast) NCI-H460 (lung) SF-268 (CNS)
0.093 0.0062
