Rakanmakilactones A–F, new cytotoxic sulfur-containing norditerpene dilactones from leaves of Podocarpus macrophyllus var. maki

Park, Hye-Jin; Yoda, Naoki; Fukaya, Haruhiko; Aoyagi, Yutaka; Takeya, Koichi

doi:10.1016/j.tet.2003.10.083

Cited by 27 publications

(16 citation statements)

References 18 publications

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“…The molecular formula was determined to be C 20 Hand 13 C-NMR spectra implied that 10 also had the desisopropylnagilactone G unit, that C-3 was linked to oxygen, and that the sulfoxide-containing C-14 side chain structure was the same as that in podolactone D (24) 5) or in rakanmakilactone D (25), 6) also isolated in the present study. The proton signal H-3 (d H 3.82) correlated with both H-5 (d H 1.89) and Me-18 (d H 1.54) in the NOESY spectrum, suggesting that OH-3 was b-oriented.…”

supporting

confidence: 58%

“…[1][2][3][4] In our recent study, several bisnor-and norditerpenoids having potent cytotoxic activities against P388 murine leukemia cells were isolated and their structures were determined. [5][6][7] In the present study, from the root and bark of this plant, we isolated fourteen new bisnor-and norditerpenoides, makilactones E-R, along with thirteen known ones. This paper describes the isolation and structural elucidation of those new bisnor-and norditerpenoides, revision of the structures of two of the thirteen known ones isolated and their cytotoxic activities.…”

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confidence: 99%

“…These observations showed that when C-14 side chain is removed, 1 had the same carbon skeleton structure as 17 8) (hereafter, this basic carbon skeleton structure is referred to as "desisopropylnagilactone G unit"). The Table 1. 1 H-NMR Data of New (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and Known (15)(16)(17) Bisnor-and Norditerpenoids Position Nagilactone G (17) Makilactone I (5) …”

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confidence: 99%

“…6) ferences between them in the new makilactones N-R (10-14) and known norditerpenoids having a sulfoxide-containing C-14 side chain, podolactone D (24) and rakanmakilactones C (27) and D (25) isolated in the present study, and four reference norditerpenoids having a C-14 side chain of this type whose sulfur configuration is properly defined, rakanmakilactones E (32), and F (28), podolactone C (30) and S R -podolactone D (33). In 10, 11, 24, 25, 27, 32, and 33, the configurations of sulfur in the sulfoxide group and C-15 have been verified directly by the single crystal X-ray crystallographic analysis.…”

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Cytotoxic Bisnor- and Norditerpene Dilactones Having 7.ALPHA.,8.ALPHA.-Epoxy-9,11-enolide Substructure from Podocarpus macrophyllus D. DON

Sato

Inaba

Park

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Podocarpus macrophyllus D. DON (Podocarpaceae) (Japanese name: Inumaki) is a dioecious evergreen tree distributed in the subtropical areas of south eastern China, Taiwan, and Japan. From this plant, flavonoids, bisflavonoids, norditerpenoids, and ecdysons have been obtained. [1][2][3][4] In our recent study, several bisnor-and norditerpenoids having potent cytotoxic activities against P388 murine leukemia cells were isolated and their structures were determined. [5][6][7] In the present study, from the root and bark of this plant, we isolated fourteen new bisnor-and norditerpenoides, makilactones E-R, along with thirteen known ones. This paper describes the isolation and structural elucidation of those new bisnor-and norditerpenoides, revision of the structures of two of the thirteen known ones isolated and their cytotoxic activities. Results and DiscussionDried root of Podocarpus macrophyllus D. DON (22.66 kg) was extracted with MeOH (45 lϫ3) at room temperature. The combined MeOH extract was concentrated and the residue (614 g) was subjected to Diaion ® HP-20 resin column chromatography (10 cmϫ40 cm) eluting sequentially with [ (18) Table 2, the 13 C-NMR spectrum of 1 was very similar to that of nagilactone G (17), a known norditerpenoid also isolated from the bark of this plant, excepting for the signals due to the C-14 side chain and C-1, C-2, and C-3 of ring A substructures. Two of the three methyl carbon signals at d C 22.3 and d C 26.1 correlating with the singlet proton signals at d H 1.64 and 2.00, respectively, in the heteronuclear multiple quantum correlation (HMQC) spectrum, were assigned to C-18 and C-20, respectively. The other methyl carbon signal (d C 21.0) correlating with the doublet methyl signal at d H 1.57 was assigned to C-17 of the side chain in the HMQC spectrum. The proton signal of Me-20 (d H 2.00) correlated with C-1 (d C 63.6) and that of Me-18 (d H 1.64) with C-3 (d C 71.4) in heteronuclear multiple bond connectivity (HMBC). In the nuclear Overhauser effect spectroscopy (NOESY) spectrum, the proton signal of Me-20 (d H 2.00) correlated with H-7 (d H 5.18). These observations showed that when C-14 side chain is removed, 1 had the same carbon skeleton structure as 17 8) (hereafter, this basic carbon skeleton structure is referred to as "desisopropylnagilactone G unit"). The 13 C-NMR spectrum showed that none of C-1, C-2 and C-3 was methylene carbon. In the correlation spectroscopy (COSY) spectrum, the proton signals H- Fourteen new bisnor-and norditerpene dilactones, makilactones E-R, having a 7a a : 8a a-epoxy-9,11-enolide substructure, were isolated from a methanolic extract of the root and the bark of Podocarpus macrophyllus D. DON (Podocarpaceae) with thirteen known bisnor-and norditerpenoids, and the structures of those new bisnorand norditerpenoids were determined on the basis of their spectroscopic studies. Of the thirteen known ones isolated, the structures of two, i.e., podolactone B and inumakilactone B, were revised on the basis of X-ray crystallographic analysis and spectro...

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confidence: 58%

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cytotoxic Bisnor- and Norditerpene Dilactones Having 7.ALPHA.,8.ALPHA.-Epoxy-9,11-enolide Substructure from Podocarpus macrophyllus D. DON

Sato

Inaba

Park

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…maki (Japanese name: Rakanmaki), norditerpenes and totarols having cytotoxic activities against P388 murine leukemia cells have been reported by us. [5][6][7] In the present study, from the bark of Podocarpus macrophyllus D. DON, we isolated 8 new diterpenes along with known ones. This paper describes the isolation and structural elucidation of these new diterpenes and their antibacterial activities against oral pathogenic microorganisms.…”

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Antibacterial Novel Phenolic Diterpenes from Podocarpus macrophyllus D. DON

Sato

Sugawara

Takeuchi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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and from the leaves of Podocarpus macrophyllus var. maki (Japanese name: Rakanmaki), norditerpenes and totarols having cytotoxic activities against P388 murine leukemia cells have been reported by us. [5][6][7] In the present study, from the bark of Podocarpus macrophyllus D. DON, we isolated 8 new diterpenes along with known ones. This paper describes the isolation and structural elucidation of these new diterpenes and their antibacterial activities against oral pathogenic microorganisms. Results and DiscussionBy sequential Diaion ® HP-20 column chromatography (H 2 O-MeOH) and silica gel column chromatography (CHCl 3 -MeOH) and the following repeated reversed-phase HPLC (MeCN-H 2 O, MeOH-H 2 O), a hot methanol extract of the bark of Podocarpus macrophyllus D. DON gave 8 new diterpene compounds (1-8) along with known lambertic acid (9), 8) 4b-carboxy-19-nortotarol (10), 8) totaradiol (11), 8) and macrophyllic acid (12). 9) Compound 1 was isolated as a colorless amorphous solid with [a] D ϩ262.6°(CHCl 3 ) and mp 124-126°C. The molecular formula was determined to be C 20 H 28 O 3 from the [M ϩ ϩNa] ion peak at m/z 339.1927 in HR-ESI-MS, implying the presence of 7 degrees of unsaturation. The IR absorption spectrum showed bands of carbonyl (1694 cm Ϫ1 ) and hydroxyl groups (3376 cm Ϫ1 ). The 1 H-and 13 C-NMR spectra of 1 (Table 1) . These data and the molecular formula suggested that 1 was an isomer of a known diterpene, 4b-carboxy-19-nortotarol (10) obtained also from this material. The heteronuclear multiple bond coherence (HMBC) correlations observed between the hydrogens H-15, H16, H-17 and the carbon C-12, and between the hydrogens H-14, H15, H-16 and the carbon C-13 indicated that the isopropyl group was at C-12 and the phenolic hydroxyl group at C-13. Further HMBC correlations between the hydrogens H-3 and H-18 and the carbonyl carbon C-19 showed that the carboxyl group was at C-4. The nuclear Overhauser effect (NOE)s between the methine proton H-5 and both the methyl protons H-18 and H-1a, respectively, and between the methyl protons H-20 and H-1b implied that the ring junction of A/B was trans and the stereochemistry of the methyl group attached to C-4 was a-oriented (Fig. 2). Hence, 1 was concluded to be 13-hydroxy-12-isopropyl-8,11,13-podocarpatrien-19-oic acid and was named inumakiol A. Only very few 12-isopropyl diterpenes are known and 1 was shown to be an analogue of such 12-isopropyl diterpene, sempervirol, 10) whose methyl group at C-4 is replaced by a carboxy group (Fig. 1).2 was isolated as a colorless amorphous solid with [a] D ϩ11.0°(CHCl 3 ) and mp 228-233°C. The molecular formula was determined to be C 20 H 28 O 3 from the [M ϩ ϩNa] ion peak at m/z 339.1895 in HR-ESI-MS, implying the presence of 7 degrees of unsaturation. The IR absorption spectrum showed bands of carbonyl (1646 cm Ϫ1 ) and hydroxyl groups (3432 cm Ϫ1 ). The 1 H-and 13 C-NMR spectra of 2 showed the presence of an isopropyl group [d C 28.5 (d), 22.7 (q), 22.6 (q) and d Table 1). The HMBC correlations observed between the hyd...

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Coupling of Sterically Hindered Trisubstituted Olefins and Benzocyclobutenones by CC Activation: Total Synthesis and Structural Revision of Cycloinumakiol

Dong

2014

Angewandte Chemie

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The first total syntheses of the proposed structure of cycloinumakiol (1) and its C5 epimer (18) are achieved in a concise and efficient fashion. Starting from the known 3‐hydroxybenzocyclobutenone, 1 and 18 are obtained in nine and five steps with overall yields of 15 % and 33 %, respectively. The key for the success of this approach is the use of a catalytic CC activation strategy for constructing the tetracyclic core of 1 through carboacylation of a sterically hindered trisubstituted olefin with benzocyclobutenone. In addition, the structure of the natural cycloinumakiol was reassigned to 19‐hydroxytotarol (7) through X‐ray diffraction analysis. This work demonstrates the potential of CC activation for streamlining complex natural product synthesis.

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Rakanmakilactones A–F, new cytotoxic sulfur-containing norditerpene dilactones from leaves of Podocarpus macrophyllus var. maki

Cited by 27 publications

References 18 publications

Cytotoxic Bisnor- and Norditerpene Dilactones Having 7.ALPHA.,8.ALPHA.-Epoxy-9,11-enolide Substructure from Podocarpus macrophyllus D. DON

Cytotoxic Bisnor- and Norditerpene Dilactones Having 7.ALPHA.,8.ALPHA.-Epoxy-9,11-enolide Substructure from Podocarpus macrophyllus D. DON

Antibacterial Novel Phenolic Diterpenes from Podocarpus macrophyllus D. DON

Coupling of Sterically Hindered Trisubstituted Olefins and Benzocyclobutenones by CC Activation: Total Synthesis and Structural Revision of Cycloinumakiol

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