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Antimycobacterial Natural Products from Marine Pseudopterogorgia elisabethae Estibaliz Sansinenea* and Aurelio Ortiz Facultad de Ciencias Químicas de la Benemérita Universidad Autónoma de Puebla, Puebla Pue., 72570, México Abstract: Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), which has been and still remains a serious disease to the global human population causing millions of deaths worldwide. The recent increase in the number of multi-drug resistant clinical isolates of M. tuberculosis has created an urgent need for the discovery and development of new antituberculosis drugs. The recent researches focusing on natural products have shown potential to obtain a potentially rich source of drug candidates. The natural products can be isolated from many sources, such as fungi, bacteria, plants and marine organisms. Among marine organisms, Pseudopterogorgia elisaEstibaliz Sansinenea bethae is capable of performing a great diversity of compounds with remarkable biological activities. Many compounds of serrulatane, amphilectane, elisabethane, and elisapterane type are produced by this organism, as well as further derivatives which exhibit antituberculosis activity. This review covers all the compounds produced by this organism that has demonstrated moderate to high activity in bioassays realized in vitro against M. tuberculosis.
Keywords: Tuberculosis, antitubercular natural products, Pseudopterogorgia elisabethae. 1. INTRODUCTION Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a disease which remains a serious threat to global human population. It is estimated that one third of the world population is infected with the bacterium bacillus. Tuberculosis (TB) is a particularly devastating worldwide problem whose control is complicated by a number of confounding features. [1]. The slow growth of M. tuberculosis on laboratory media results in nine weeks for definitive diagnosis and another six weeks are to determine the most appropriate antibiotic therapy. Therefore, four to six months are required to complete this process establishing a good treatment; however, many patients with tuberculosis will die during this time period. The long duration and the secondary effects due to the administrated drugs cause the patients to abandon treatment before finishing it, which contributes to the spread of TB,leading to the emergence of new multidrug resistant strains. The treatment of TB is further complicated by the increasing occurrence of strains resistant to multiple drugs. Multidrug-resistant tuberculosis (MDRTB) is strictly defined as M. tuberculosis strains showing resistance simultaneously against isoniazid and rifampicin, which are the standards drugs. The emergence of new cases, increased incidence of multidrug resistant strains, adverse effects of first- and second-line antituberculosis drugs, and increased incidence of tuberculosis associated with viral infections (Human Immunodeficiency Virus, HIV) which have led to renewed research interest in natural products for discovering new antitubercular agents. Natural products play an important role in medicine and the discovery of drugs. Therefore, it is important to identify organisms which could be a source of novel natural products and, in particular, antitubercular compounds [2-6]. In this sense, gorgonian corals, such as Pseudopterogorgia elisabethae (Bayer, 1961) have attracted the attention of many researchers due to a variety of novel bioactive secondary metabolites which have shown considerable bioactivities. There are some reviews which have revised some antitubercular natural products from diverse natural sources [2-6]. Some others have reviewed the natural products isolated from Pseudoterogorgiae elisabethae with differ-
*Address correspondence to these authors at the Facultad de Ciencias Químicas de la Benemérita Universidad Autónoma de Puebla, Puebla Pue., 72570, México; Tel 00-52222-2295500 ext 7518; Fax: 2295584; E-mail:
[email protected] 1570-1794/16 $58.00+.00
ent biological activities [8-10] and there is a review which more specifically where discusses only diterpenes isolated from gorgonian corals with different biological activities [7]. Here, we summarize the compounds isolated from Pseudopterogorgia elisabethae with good antitubercular activity till date. 2. PSEUDOPTEROGORGIA ELISABETHAE Pseudopterogorgia species are the most common of the Caribbean species with over fifteen documented. Tropical reefs are often dominated by these organisms, whose taxonomic identifications have been described as ‘‘perplexing and often exasperating’’ by F. M. Bayer (1961) the author of ‘The shallow-water octocorallia of the West Indian region’ [7]. Pseudopterogorgia elisabethae is found in the tropical western Atlantic, including Florida, Bahamas, Cuba, Jamaica, Honduras, Belize, and Mexico. This specie is less than one meter tall. Its side branches may be pinnate (paired on opposite sides of the main branches) but often are not pinnate. Pseudopterogorgia elisabethae is moderately slim, and is best characterized as “sea plumes” based on their large, highly branched (plumose), and physically soft forms, as shown in Fig. (1) [8].
Fig. (1). Pseudopterogorgia elisabethae. © 2016 Bentham Science Publishers
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In the 1990s, this specie was used extensively for investigating unusual organic compounds which have pharmacological activity. For nearly four decades, investigations into the natural products chemistry of Caribbean gorgonian octocorals of the genus Pseudopterogorgia have yielded a plethora of diterpenoids of diverse molecular architectures with remarkable biological activities [9]. The gorgonian species P. bipinnata, P. kallos, P. acerosa, P. americana, and P. elisabethae are particularly rich for the production of the vast majority of these fascinating natural products [10]. Recently, the number of diterpenoid skeletal classes produced by these chemically prolific Pseudopterogorgia species has increased. Furthermore, many of the metabolites engendered by these animals are liable to experience subsequent rearrangement to yield even more perplexing structural variants [8]. The chemical investigation of these octocoral species has led to important pharmacological advances which in turn have stimulated novel synthetic methodologies and inspired many chemists and biochemists to speculate on the plausible biogenetic relationships among the diverse skeletal families of diterpenes that are routinely coisolated from them [11]. As part of a continuous effort to discover new antituberculosis agents from marine sources, Rodriguez et al. reported the isolation, structure elucidation, and biological properties of a great number of novel marine metabolites from Pseudopterogorgia elisabethae. [10]. Pseudopterosins, for example, are potent anti-inflammatory and analgesic agents that have been licensed to a small pharmaceutical firm for medical use as potential anti-inflammatory drugs. Unprocessed pseudopterosin extract, however, has already found its way to the marketplace and is currently being used as an additive to prevent irritation caused by exposure to the sun or chemicals in the Estée Lauder cosmetic skin care product Resilience® [12]. Collected samples were extracted with CH2Cl2/MeOH, and after filtra-
tion, the crude extract was evaporated under reduced pressure. The extract was then partitioned between hexane and H2O, and the resulting organic extract was concentrated in vacuum to yield oil. Extensive chromatography afforded a large number of compounds in varying structures but small quantities. The yields based on the dry weight of prepurified hexane fractions were between 0.001 and 0.01% [8, 13]. The organism Pseudopterogorgia elisabethae is capable of performing a kind of diversity oriented synthesis creating stereochemical and structural complexity from simple precursors. The intricate molecular architecture of these natural products also caught the attention of synthetic chemists. Compounds from Pseudopterogorgia elisabethae can be classified according to their carbon skeletons and a good classification and examples with different biological activities are described in a Heckrodt and Mulzer’s review [8]. 3. ANTIMYCOBACTERIAL NATURAL PRODUCTS FROM PSEUDOPTEROGORGIA ELISABETHAE Many compounds of serrulatane, amphilectane, elisabethane, and elisapterane type as well as further derivatives exhibiting antituberculosis activity. Since the pioneering work of the Fenical group in the 1980’s [14, 15], the molecular architecture and potent pharmacological activities of the compounds extracted from the Caribbean gorgonian Pseudopterogorgia elisabethae, have sparked great interest [8, 10, 12]. Typical values for growth inhibition of Mycobacterium tuberculosis range between 20 and 60%. However, some of these marine diterpene compounds show very high growth inhibition rate. The synthesis of many of them has been reported and reviewed previously [6]. In the Table 1, there is a classification of all antitubercular compounds that are revised in this review.
Table 1. A classification of the antitubercular compounds isolated from Pseudoterogorgia elisabethae. Serial Number
Chemical Structure
1
MIC (μg/mL)
Synthesis Available
12.5
Yes
12.5
No
12.5
No
2
3
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Table 1. contd…
Serial Number
Chemical Structure
4
MIC (μg/mL)
Synthesis Available
12.5
Yes
12.5
Yes
12.5
Yes
12.5
Yes
12.5
Yes
5
6
7
8
4
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Table 1. contd…
Serial Number
Chemical Structure
MIC (μg/mL)
9
12.5
Synthesis Available
No
No 10
12.5
No 11
12.5
12
6.25
13
6.25
No
No
Antimycobacterial Natural Products from Marine Pseudopterogorgia elisabethae
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Table 1. contd…
MIC (μg/mL)
Synthesis Available
14
6.25
No
15
6.25
No
16
6.25
No
17
128
Yes
18
63
No
19
6.25
Serial Number
Chemical Structure
No
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Table 1. contd…
Serial Number
Chemical Structure
MIC (μg/mL)
Synthesis Available
No 20
12.5
21
12.5
No
22
61
No
23
61
No
24
6.25
No
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Table 1. contd…
MIC (μg/mL)
Synthesis Available
25
12.5
No
26
6.25
No
27
6.25
No
28
6.25
No
29
6.25
No
Serial Number
Chemical Structure
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Table 1. contd…
MIC (μg/mL)
Synthesis Available
30
6.25
No
31*
0.5
Yes
0.1
Yes
4.0
Yes
2.0
Yes
Serial Number
Chemical Structure
Rifampin
32* Isoniazid
33*
Ethambutol
34*
Streptomycin *Standard anti-TB drugs against Mycobacterium tuberculosis
Rodriguez et al., isolated two active metabolites, pseudopteroxazole 1 and seco-pseudopteroxazole 2, from the hexane extracts of the West Indian gorgonian coral Pseudopterogorgia elisabethae which exhibited anti-tuberculosis activity [16] with MIC of 12.5 μg/mL. Seco-Pseudopteroxazole 2, which was isolated as a minor constituent, is assumed to be a logical biogenetic precursor to 1 (or vice versa) upon undergoing further dehydrogen-coupling at the C5-C13 positions. The synthesis of pseudopteroxazole 1 and its diastereomers was described by Corey [17, 18]. A related metabolite, homopseudopteroxazole 3, was isolated as a minor constituent of the hexane extract showing a strong inhibition activity for Mycobacterium tuberculosis [19] (Fig. 2). Semi synthetic pseudopteroxazoles were synthesized and probed their antimycobacterial activity against Mycobacterium tuberculosis [20].
Elisabethin C 4 is a novel bisnor-diterpenoid which was isolated from the gorgonian Pseudopterogorgia [21]. Its structure is characterized by a unique bicyclic carbon skeleton (bisnorsecoelisabethane skeleton). The compound 4 was found to have antituberculosis activity against Mycobacterium tuberculosis H37Rv (42% inhibition) of 12.5 μg/mL and its synthesis was reported in 2002 [22]. The marine diterpenoid and antitubercular elisabethin A 5 were isolated, along with their structurally related isomers elisapterosin B 6 [23] and colombiasin A 7 [24], from the chemically rich Caribbean gorgonian Pseudopterogorgia elisabethae in the late 1990s [21] with MICs of 12.5 μg/mL. The synthesis of Elisabethin A 5 was reported by Heckrodt and Mulzer [25]. Also, the syntheses of elisapterosin B 6 and colombiasin A 7 have been described [2628] (Fig. 3).
Antimycobacterial Natural Products from Marine Pseudopterogorgia elisabethae
CH3
CH3
O N
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O
CH3
9
2
N
H H3C
O
5 10
CH3
H H3C
C5H11
CH3
H
13
N
H
H3C
H3C H3C
1 Pseudopteroxazole
9
CH3
CH3
CH3 3 Homopseudopteroxazole
2 Seco-Pseudopteroxazole
Fig. (2). Pseudopteroxazole type structures. CH3 H
CH3
H3C
H3C
O
H3C
H
O
CH3
O
O H3C
CH3
Me
O
CH3
H O
OH H
O
H
O
OH Me
Me
Me
5 Elisabethin A
4 Elisabethin C
Me
H
OH
CH3
Me
Me
H
Me 7 Colombiasin A
6 Elisapterosin B
Fig. (3). Me
Me
OH
H
H
Me
H
Me
Me
Me
Me
Me
HO
HO
Me
Me
Me
Me
Me 9 7-Hydroxy-Erogorgiaene
8 Erogorgiaene
Me
Me 10 7,8-dihydroxyerogorgiaene
Fig. (4). CH3
CH3
H H3C
H H
O
Elisabanolide 11
CH3
O O
O
CH3 O
H3C
O
O O
CH3 H
CO2Et
CH3
H3C H3C
H
H3C
OH
Elisabetholide 12
H3C
O H
H3C Amphilectolide 13
Fig. (5).
Another antituberculotic diterpenoid isolated from gorgonian Pseudopterogorgia elisabethae is erogorgiaene 8 [29] with an MIC of 12.5 μg/mL. The major challenge associated with its synthesis lies in the control of the stereocenters, since this molecule lacks functional groups near the stereogenic centers. The excellent biological activity and extreme scarcity of erogorgiaene from the natural source, have attracted significant interest among synthetic chemists, and so far, four total syntheses have been reported [30-33]. Oxidation products of this aromatic hydrocarbon were shown to be 7-hydroxyerogorgiaene 9 [29] and 7,8-dihydroxyerogorgiaene 10 which are intermediates in the pseudopterosins biosynthesis pathway [34] (Fig. 4).
Elisabanolide 11 was proposed on the basis of spectral data analysis, chemical transformations and X-ray crystallographic analysis and showed weak antituberculosis activity in vitro [35]. Two new tricyclic lactones, elisabetholide 12 and amphilectolide 13, were reported from a Colombian specimen of P. elisabethae, with weak antituberculosis activity [36] (Fig. 5). The structures of two novel nor-diterpenes, sandresolides A 14, B 15 and C 16, were reported by Rodriguez and co-workers [37, 38] with inhibition against Mycobacterium tuberculosis H37Rv at a concentration of 6.25 μg/mL. The synthesis of sandresolide B 15 has recently been reported together with the synthesis of amphilectolide 13 [39] (Fig. 6).
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CH3
Sansinenea and Ortiz
CH3
H
H H3C
HO CH3
OH
CH3
H
H3C
O
HO CH3
OH
H
O
O
CH3
HO H3C
O
O
O
Sandresolide A
Sandresolide B
Sandresolide C
14
15
16
Fig. (6). H3C
H3C
H
H H
10 2 1 11 9 HO 6 8 3 12 7 1314 4 5 18
OH CH3 CH3 HO
O
H3C
CH3
O
19
Caribenol A
O
Caribenol B
17
18
Fig. (7). H3C
H3C
H H
H
O
H OH
H3C OH Cumbiasin A 19
H3C
H
CH3
H H
O
OH
O OH
O
H3C OH Cumbiasin B 20
CH3
O O
H2C H3C
H
O HO
CH3
CH3 O
Cumbiasin C 21
Fig. (8).
The extraction of two specimens of Pseudopterogorgia elisabethae, each collected from a different location at the San Andre´s Archipelago, afforded two new norditerpenes, caribenols A 17 and B 18. Caribenols A 17 and B 18 were elucidated by a combination of single crystal X-ray analysis and comprehensive 2D NMR measurements and they have MIC values of >128 μg/mL and 63 μg/mL, respectively [40] (Fig. 7). Caribenol A 17 has an unprecedented tricarbocyclic ring system. It carries three all-cis methyl groups at the C1, C4, and C8 positions and a 5-hydroxyfuran-2(5H)-one motif, posing a particularly synthetic challenge. Indeed, efforts have been directed toward exploring feasible strategies for the chemical syntheses of these scarce yet pharmacologically significant natural substances. Therefore, the asymmetric total synthesis of caribenol A 17 compound has been reported [41]. From the hexane extract of the West Indian gorgonian Pseudopterogorgia elisabethae, two diterpenes, cumbiasins A 19 and B 20, having a novel tetracyclic carbon skeleton named cumbiane, were isolated, which displayed mild in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv. In addition, they isolated cumbiasin C 21, a ring cleavage product of cumbiasin B 20 that possesses an unusual carbocyclic framework named secocumbiane which also shows mild antituberculosis activity [42] (Fig. 8). The tetracyclic ring system of cumbiasin was synthesized by a Diels–Alder reaction followed by tandem ring forming reactions from an alpha-keto radical [43] and the (6,6,5)-tricyclic ring was achieved by a enantiospecific stereoselective synthesis [44]. Ileabethin 22, which was isolated in 2002, contains an unprecedented perhydroacenaphthene carbon skeleton which appears to be
biosynthetically related to the serrulatane (biflorane) skeleton. Besides a new carbon skeleton, ileabethin 22 possesses several unusual structural features. On the one hand, there is a fully substituted aromatic ring, whose substitution pattern resembles that of the pseudopterosin class of diterpene-glycosides, and on the other hand, the isobutenyl side chain found typically in many P. elisabethae metabolites appear in 22 masked spiro gem-dimethyl dihydrofuran moiety [45]. Ileabethoxazole 23, a new perhydroacenaphthene-type diterpene alkaloid containing a benzoxazole moiety has been reported, displaying activity against Mycobacterium tuberculosis (H37Rv) with an MIC of 61 μg/mL [46]. After extensive use of two-dimensional NMR techniques, it was found that the molecule is based on the same ileabethane diterpenoid skeleton as ileabethin 22 (Fig. 9). An unusual compound possessing a new class of C15rearranged pentanorditerpene, named elisabethin H 24 and isolated from the Caribbean Sea whip Pseudopterogorgia elisabethae, was shown to inhibit 51% of mycobacterial growth (H37Rv strain) at 6.25 mg/mL [38]. In the same study the compound elisabethadienol 25 was isolated as a bicyclic diterpenoid which inhibit the growth of Mycobacterium tuberculosis 28% at 6.25 mg/mL [38] (Fig. 10). Interpretation of the NMR spectral features indicated that the skeleton of elisabethadienol 25 was similar to that of (–)elisabethatrienol, a suspected biosynthetic intermediate in the important series of anti-inflammatory diterpene glycosides known as the pseudopterosins. Pseudopterosins are tricyclic diterpene glycosides isolated from the Caribbean Sea whip (gorgonian) Pseudopterogorgia elisabethae (Gorgoniidae). They are potent anti-inflammatory [47] and analgesic agents that have been licensed to a small pharmaceutical firm,
Antimycobacterial Natural Products from Marine Pseudopterogorgia elisabethae
Current Organic Synthesis, 2016, Vol. 13, No. ??
CH3
CH3 H3C
H3C
OH H
N
H3C
CH3
H3C
O H
H
OCH3
H3C
11
HO
CH3
H CH3
Ileabethin
Ileabethoxazole
22
23
Fig. (9). CH3 OH
CH3 H3C
H
H
H O
CH3
H O
H3C
OH
H3C
CH3
H3C
CH3
CH3 Elisabethin H
Elisabethadienol
24
25
Fig. (10). CH3 H3C
CH3
OH
H3C
OH
H
H O
H3C
O
OR1
H3C H
H3C
OR2
H3C R1O
O CH3
CH3
OR3
Pseudopterosin P 26 R3= Ac; R1 = R2 = H Pseudopterosin Q 27 R2= Ac; R1 = R3 = H
O R2O
OR3
Pseudopterosin U 28 R3= Ac; R1 = R2 = H Pseudopterosin V 29 R2= Ac; R1 = R3 = H CH3
H3C
OH H O
H3C
H3C R1O CH3
O R 2O
OR3
Seco-pseudopterosin H 30 R3= Ac; R1 = R2 = H Seco-pseudopterosin I 31 R1= Ac; R2 = R3 = H
Fig. (11).
Osteoarthritis Sciences Inc., for medical use as potential antiinflammatory drugs. In addition, the pseudopterosins extract has found its way to the marketplace. It is used as an additive to prevent irritation caused by exposure to the sun or the chemicals in the Estée Lauder cosmetic skin care product, Resilience [12].
U 28, and V 29 marginally inhibited 37%, 43%, and 25% of mycobacterial growth, respectively. On the other hand, secopseudopterosins H 30 and I 31 induced, respectively, 25% and 37% of mycobacterial growth at the same concentration [49] (Fig. 11).
However, pseudopterosins P 26, Q 27, U 28, V 29 [48, 49] and seco-Pseudopterosins H 30 and I 31 were tested for their inhibitory activity toward the growth of Mycobacterium tuberculosis H37Rv at a concentration of 6.25 μg/mL. Pseudopterosin P 26 exhibited the strongest inhibitory activity (76%), whereas pseudopterosins Q 27,
Elisabatins A 32 and B 33 are two novel amphilectane type diterpenoids isolated from hexane extracts of P. elisabethae collected in San Andres Island, Colombia [50]. A little inhibition was measured in vitro testing at 6.25 μg/mL against Mycobacterium tuberculosis [51] (Fig. 12).
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HO
Sansinenea and Ortiz
CH3
CH3
H3C
O
H3C
O
OH
O H3C
CH3 CH3
Elisabatin A 32
H3C
[12] [13]
[14]
CH3 [15]
CH3 Elisabatin B 33
[16]
Fig. (12).
[17]
4. CONCLUDING REMARKS
[18]
Natural products traditionally have played a pivotal role in drug discovery and in particular the uniqueness of marine metabolite core structures makes these compounds of interest in the development of pharmaceutical agents, in particular the antimycobacterials discussed here. Significant advances in parasitological and biochemical researches on tuberculosis have been made in the past few decades, but the available treatment options are far from satisfactory. To eliminate this problem from every corner of the world, a safe, non-toxic and cost-effective drug with novel mode of action is urgently required. Since 1998, extensive attention has been given to the chemically rich species of Pseudopterogorgia elisabethae which produce many of natural products with antitubercular activity. A number of compounds covered in this review possess in vitro antimycobacterial activities comparable to standard anti-TB drugs. The synthesis of many of them has been not reported yet. Further investigations are needed leading to the development of new antituberculosis drugs including the synthesis of these compounds. CONFLICT OF INTEREST
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
The authors confirm that this article content has no conflict of interest. [27]
ACKNOWLEDGMENTS We thank VIEP (project) for financial support. REFERENCES [1] [2]
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Received: June 08, 2015
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Revised: October 19, 2015
Accepted: November 10, 2015
