Die Konstitution des Alkaloids Cryptolepin

Gellért, E.; Raymond-Hamet,; Schlittler, E.

doi:10.1002/hlca.19510340228

Cited by 101 publications

(61 citation statements)

References 8 publications

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“…As an activator of p21 WAF1/CIP1 promoter activity, we isolated cryptolepine (CLP: 5-methyl indolo (2,3b)-quiniine), an indoloquinoline alkaloid, from the traditional Ayurvedic medicinal plant Sida cordifolia. CLP was first isolated from Cryptolepis sanguinolenta (24) that is native to Central and West Anti-malaria activity of CLP was reported previously (26). In addition, it has been reported that CLP can suppress the growth of cancer cells in vitro by inhibiting cell cycle progression and causing apoptosis in human HL-60 leukemia (27) and B16 melanoma cells (28,29).…”

Section: Introductionmentioning

confidence: 99%

The plant alkaloid cryptolepine induces p21WAF1/CIP1 and cell cycle arrest in a human osteosarcoma cell line

Matsui

Sowa²,

Murata³

et al. 2007

Int J Oncol

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Abstract. We previously established a bioassay method to screen for compounds that activate the promoter activity of p21 WAF1/CIP1 , a potent inhibitor of cyclin-dependent kinases, in a p53-independent manner. As an activator of p21 WAF1/CIP1promoter activity, we isolated cryptolepine (CLP: 5-methyl indolo (2,3b)-quiniine), an indoloquinoline alkaloid, from the traditional Ayurvedic medicinal plant Sida cordifolia. We show here that CLP induces the expression of p21 WAF1/CIP1with growth arrest in p53-mutated human osteosarcoma MG63 cells. Four micromolar of CLP completely inhibited the growth of MG63 cells and caused G 2 /M-phase arrest. CLP up-regulated the expression of p21 WAF1/CIP1 at both mRNA and protein levels in a dose-dependent manner. Using several mutant p21 WAF1/CIP1 promoter constructs, we found that the CLP-responsive element is an Sp1 site at -82 relative to the transcription start site of the p21 WAF1/CIP1 promoter. These findings suggest that CLP arrests the growth of MG63 cells by activating the p21 WAF1/CIP1 promoter through the specific Sp1 site in a p53-independent manner. In addition, CLPmediated cell cycle arrest was reduced by the knockout of the p21 WAF1/CIP1 gene in human colon cancer HCT116 cells, suggesting that the cell cycle arrest by CLP was at least partially mediated through the induction of p21expression. Although we need further study of chemotherapeutic effect in vivo, these results raise the possibility that CLP might be a suitable chemotherapeutic agent for treatment of osteosarcoma. IntroductionOsteosarcoma is the most common form of primary malignant bone tumor that mainly occurs in juvenile patients. Although the development of effective adjuvant regimen of chemotherapy has substantially improved the prognosis of patients (1-4), >20% of patients still die as a result of tumor metastasis (5-10). One of the most serious causes of therapeutic failure is the resistance of the tumor cells to chemotherapeutic agents (11,12). To overcome the drug resistance, new anti-tumor agents or chemicals and new anti-tumor therapeutic approaches need to be developed. p21 WAF1/CIP1 is a member of the cyclin-dependent kinase inhibitors and induces G 1 -and G 2 /M-phase cell cycle arrest (13-16). p21 WAF1/CIP1 induces differentiation of both normal and transformed cells and suppresses the growth of malignant cells, in vitro and in vivo (17,18 WAF1/CIP1 is an attractive molecular target to suppress cell growth even in p53-mutated cancer cells and p21 WAF1/CIP1 -inducing agents by a p53-independent pathway might be effective for chemotherapy of osteosarcoma with poor prognosis.Recently, we established a bioassay method using p53-negative human osteosarcoma MG63 cells to screen for compounds that activate the p21 WAF1/CIP1 promoter activity in a p53-independent manner (23). As an activator of p21 WAF1/CIP1 promoter activity, we isolated cryptolepine (CLP: 5-methyl indolo (2,3b)-quiniine), an indoloquinoline alkaloid, from the traditional Ayurvedic medicinal plant Sida cordifolia. CLP was first is...

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Section: Introductionmentioning

confidence: 99%

The plant alkaloid cryptolepine induces p21WAF1/CIP1 and cell cycle arrest in a human osteosarcoma cell line

Matsui

Sowa²,

Murata³

et al. 2007

Int J Oncol

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“…315,316 The total synthesis of 336 was achieved as illustrated in Scheme 72. The total synthesis started from coupling of 1,5-naphthalenediol mono-methoxymethyl (MOM) ether 329 with bromobenzoquinone 330 mediated by K 2 CO 3 in DMSO 317 to afford a C-O coupling product.…”

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confidence: 99%

Total synthesis of natural products containing benzofuran rings

et al. 2017

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Research on natural products containing benzofuran has remarkably increased during the past few decades.Newly isolated natural products with complex structures are being studied, characterized and screened for possible biological activities. Several of such compounds have exhibited various biological activities, thus their total syntheses have attracted much attention from synthetic organic chemists. In this review, we aim to highlight the origins, structures, biological potencies, and synthetic approaches of those natural products bearing at least one benzofuran in their complex structures. Furthermore, we especially focus on the step in which this key heterocycle is installed during the total synthesis of a natural product as the desired target.

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“…To compound 13 (1 mmol) in ethanol (10 mL) was added sodium hydroxide (100 mL, 10% w/v) and the mixture refluxed for 2h in a 100 o C oil bath. The cooled mixture was extracted with chloroform (50mL×5), and the extract was dried over MgSO 4 . After removal of the solvent, the residue was chromatographed on silica gel, eluting with light petroleum and ethyl acetate (3:1 to 1:1) to give indolo [3,2-b]quinoline 15 and indolo [3,2-b]quinolinone 17 as yellow solid.…”

Section: Methodsmentioning

confidence: 99%

“…(Figure 1) A number of indolo [3,2-b]quinoline and indolo [3,2-b]quinolinone alkaloids, such as quindoline 1, 1,2 quindolinone 2, 3 cryptolepine 3, 4 5-methylquindolinone 4, 1 biscryptolepine 5, 5 cryptoquindoline 6, 1 cryptomisrine 7 6 etc., had been isolated from a medicinal plant Cryptolepis Sanguinolenta in Africa. (Figure 2) Many indolo [3,2-b]quinoline and indolo [3,2-b]quinolinone derivatives, especially the 11-substituted indolo [3,2-b]quinoline, showed remarkable pharmaceutical activity.…”

Section: Introductionmentioning

confidence: 99%

The regional selective hydrolysis or hydrolytic oxidization of indolo[3,2-b]quinolinium salts: a new simple synthetic approach to substituted indolo[3,2-b]quinolinones

Cheng¹,

Jian²,

Meth‐Cohn³

2005

Arkivoc

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In this article, the regioselective hydrolysis or hydrolytic oxidation of indolo[3,2-b]quinolinium salts was examined, which lead to the formation of indolo [3,2-b]quinolinone as the major product or the sole product in different conditions. This work provided a new method for the preparation of substituted indolo [3,2-b]quinolinones. Keywords: Indolo[3,2-b]quinolinium salt, indolo[3,2-b]quinolinone, hydrolysis, hydrolytic oxidation IntroductionIndolo [3,2-b]quinolines 1 and indolo [3,2-b]quinolinones 2 are sometimes referred in the literature to as quindolines and quindolinone, respectively. (Figure 1) A number of indolo [3,2-b]quinoline and indolo [3,2-b]quinolinone alkaloids, such as quindoline 1, 1,2 quindolinone 2, 3 cryptolepine 3, 4 5-methylquindolinone 4, 1 biscryptolepine 5, 5 cryptoquindoline 6, 1 cryptomisrine 7 6 etc., had been isolated from a medicinal plant Cryptolepis Sanguinolenta in Africa. (Figure 2) Many indolo [3,2-b]quinoline and indolo [3,2-b]quinolinone derivatives, especially the 11-substituted indolo [3,2-b]quinoline, showed remarkable pharmaceutical activity. For example, 11-[2-methoxy-4-(methylsulfonyl)phenyl]amino indoloquinoline 8 has shown to exhibit antitumor activity, 7,8 while both 11-(4-diethylamino)-2-methylbutylamino indoloquinoline 9 9 and 11-(4-hydroxylphenyl)amino indoloquinoline 10 10 have comparable activity with chloroquine to inhibit a multi-resistant Plasmodium falciparum strain (Figure 3). Most of the known 11-substituted indoloquinoline derivates were prepared from nucleophilic substitution of 11-chloroindoloquinoline, 7,10,11 and the later compounds could be readily obtained by treatment of indoloquinolinones with POCl 3. 7,10,12 Therefore the substituted indolo[3,2-b]quinolinones became With the purpose to synthesize the analogues of alkaloid biscryptolepine 5, cryptoquindoline 6 and cryptomisrine 7, we first need to prepare some substituted indolo [3,2-b]quinolinones as starting materials. Although some synthetic methods for the preparation of indolo [3,2-b]quinolinones have been developed, most of them started from the condensation of two o-aminoaryl carbonyl compounds. 7,12,13 Frequently encountered problems in these methods are the lack of commercially available starting materials. Several years ago, 14 we reported that the interaction of the Vilsmeier's reagents 12 and an organic base lead to the formation of 11-N-arylamino indolo[3,2-b]quinolinium salts 13 and /or indolo[3,2-b]quinolinium salts 14, and the compounds 13 or 14 could be readily demethylated by sodium iodide/ triphenylphosphine to give quindolines 15 or 16 respectively in high yields. (Scheme 1) Considering their electrophilic nature, the hydrolysis of quindolinium ions 13 and 14 would give rise to substituted quindolinones. Here we report our study on the hydrolysis or hydrolytic oxidation of indolo[3,2-b]quinolinium salts. Scheme 1 Results and DiscussionIn our earlier work, 14 we had noticed that the hydrolysis of indolo[3,2-b]quinolinium salt 13a (X = Me) in 10% NaOH aqueous solutio...

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Die Konstitution des Alkaloids Cryptolepin

Cited by 101 publications

References 8 publications

The plant alkaloid cryptolepine induces p21WAF1/CIP1 and cell cycle arrest in a human osteosarcoma cell line

The plant alkaloid cryptolepine induces p21WAF1/CIP1 and cell cycle arrest in a human osteosarcoma cell line

Total synthesis of natural products containing benzofuran rings

The regional selective hydrolysis or hydrolytic oxidization of indolo[3,2-b]quinolinium salts: a new simple synthetic approach to substituted indolo[3,2-b]quinolinones

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