Dregamine
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| Category | Others |
| Catalog number | BBF-05079 |
| CAS | 2299-26-5 |
| Molecular Weight | 354.44 |
| Molecular Formula | C21H26N2O3 |
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Description
Dregamine is a naturally occurring monoterpene indole alkaloid found in Tabernaemontana.
Specification
| Synonyms | 20-Epitabernemontanine; Tabernaemontanine; Vobasan-17-oic acid, 19,20-dihydro-3-oxo-, methyl ester, (20α)- (9CI) |
| IUPAC Name | methyl (1S,14S,15R,18S)-15-ethyl-17-methyl-12-oxo-10,17-diazatetracyclo[12.3.1.03,11.04,9]octadeca-3(11),4,6,8-tetraene-18-carboxylate |
| Canonical SMILES | CCC1CN(C2CC3=C(C(=O)CC1C2C(=O)OC)NC4=CC=CC=C34)C |
| InChI | InChI=1S/C21H26N2O3/c1-4-12-11-23(2)17-9-15-13-7-5-6-8-16(13)22-20(15)18(24)10-14(12)19(17)21(25)26-3/h5-8,12,14,17,19,22H,4,9-11H2,1-3H3/t12-,14-,17-,19-/m0/s1 |
| InChI Key | FFVRRQMGGGTQRH-YWKPPDPDSA-N |
Properties
| Appearance | Crystals |
| Boiling Point | 515.9°C at 760 mmHg |
| Density | 1.176 g/cm3 |
| Solubility | Soluble in methanol, chloroform, water |
Reference Reading
1. Exploring the Monoterpene Indole Alkaloid Scaffold for Reversing P-Glycoprotein-Mediated Multidrug Resistance in Cancer
David S P Cardoso, Nikoletta Szemerédi, Gabriella Spengler, Silva Mulhovo, Daniel J V A Dos Santos, Maria-José U Ferreira Pharmaceuticals (Basel). 2021 Aug 28;14(9):862. doi: 10.3390/ph14090862.
Dregamine (1), a major monoterpene indole alkaloid isolated from Tabernaemontana elegans, was submitted to chemical transformation of the ketone function, yielding 19 azines (3-21) and 11 semicarbazones (22-32) bearing aliphatic or aromatic substituents. Their structures were assigned mainly by 1D and 2D NMR (COSY, HMQC, and HMBC) experiments. Compounds 3-32 were evaluated as multidrug resistance (MDR) reversers through functional and chemosensitivity assays in a human ABCB1-transfected mouse T-lymphoma cell model, overexpressing P-glycoprotein. A significant increase of P-gp inhibitory activity was observed for most derivatives, mainly those containing azine moieties with aromatic substituents. Compounds with trimethoxyphenyl (17) or naphthyl motifs (18, 19) were among the most active, exhibiting strong inhibition at 0.2 µM. Moreover, most of the derivatives showed selective antiproliferative effects toward resistant cells, having a collateral sensitivity effect. In drug combination assays, all compounds showed to interact synergistically with doxorubicin. Selected compounds (12, 17, 18, 20, and 29) were evaluated in the ATPase activity assay, in which all compounds but 12 behaved as inhibitors. To gather further insights on drug-receptor interactions, in silico studies were also addressed. A QSAR model allowed us to deduce that compounds bearing bulky and lipophilic substituents were stronger P-gp inhibitors.
2. BBIT20 inhibits homologous DNA repair with disruption of the BRCA1-BARD1 interaction in breast and ovarian cancer
Liliana Raimundo, Angela Paterna, Juliana Calheiros, Joana Ribeiro, David S P Cardoso, Ilaria Piga, Susana Junqueira Neto, Denise Hegan, Peter M Glazer, Stefano Indraccolo, Silva Mulhovo, José Luís Costa, Maria-José U Ferreira, Lucília Saraiva Br J Pharmacol. 2021 Sep;178(18):3627-3647. doi: 10.1111/bph.15506. Epub 2021 Jun 11.
Background and purpose: Advances in the treatment of triple-negative breast and ovarian cancer remain challenging. In particular, resistance to the available therapy, by restoring or overexpressing the DNA repair machinery, has often been reported. New strategies to improve the therapeutic outcomes of these cancers are needed. Herein, we disclose the dregamine 5-bromo-pyridin-2-ylhydrazone (BBIT20), a natural monoterpene indole alkaloid derivative, as an inhibitor of homologous DNA repair. Experimental approach: To unveil BBIT20 antitumour activity and underlying molecular mechanism of action, two-dimensional (2D) and three-dimensional (3D) cell cultures, patient-derived cell lines and xenograft mouse models were used. Key results: BBIT20 disrupted the BRCA1-BARD1 interaction, triggering nuclear-to-cytoplasmic BRCA1 translocation, cell cycle arrest and downregulation of homologous DNA repair-related genes and proteins, with subsequent enhancement of DNA damage, reactive oxygen species generation and apoptosis, in triple-negative breast and ovarian cancer cells. BBIT20 also displayed pronounced antitumour activity in patient-derived cells and xenograft mouse models of ovarian cancer, with low toxicity in non-malignant cells and undetectable side effects in mice. Additionally, it did not induce resistance in triple-negative breast and ovarian cancer and displayed marked synergistic effects with cisplatin and olaparib (a poly [ADP-ribose] polymerase inhibitor), on 2D and 3D models of these cancer cells. Conclusion and implications: These findings add an inhibitor of the BRCA1-BARD1 interaction to the list of DNA-damaging agents. Importantly, either as a single agent or in combination therapy, BBIT20 reveals great potential in the personalized treatment of aggressive and resistant cancers, particularly triple-negative breast and advanced ovarian cancer.
3. Alkylated monoterpene indole alkaloid derivatives as potent P-glycoprotein inhibitors in resistant cancer cells
David S P Cardoso, Annamária Kincses, Márta Nové, Gabriella Spengler, Silva Mulhovo, João Aires-de-Sousa, Daniel J V A Dos Santos, Maria-José U Ferreira Eur J Med Chem. 2021 Jan 15;210:112985. doi: 10.1016/j.ejmech.2020.112985. Epub 2020 Nov 4.
Aiming at generating a series of monoterpene indole alkaloids with enhanced multidrug resistance (MDR) reversing activity in cancer, two major epimeric alkaloids isolated from Tabernaemontana elegans, tabernaemontanine (1) and dregamine (2), were derivatized by alkylation of the indole nitrogen. Twenty-six new derivatives (3-28) were prepared by reaction with different aliphatic and aromatic halides, whose structures were elucidated mainly by NMR, including 2D NMR experiments. Their MDR reversal ability was evaluated through a functional assay, using as models resistant human colon adenocarcinoma and human ABCB1-gene transfected L5178Y mouse lymphoma cells, overexpressing P-glycoprotein (P-gp), by flow cytometry. A considerable increase of activity was found for most of the derivatives, being the strongest P-gp inhibitors those sharing N-phenethyl moieties, displaying outstanding inhibitory activity, associated with weak cytotoxicity. Chemosensitivity assays were also performed in a model of combination chemotherapy in the same cell lines, by studying the in vitro interactions between the compounds and the antineoplastic drug doxorubicin. Most of the compounds have shown strong synergistic interactions with doxorubicin, highlighting their potential as MDR reversers. QSAR models were also explored for insights on drug-receptor interaction, and it was found that lipophilicity and bulkiness features were associated with inhibitory activity, although linear correlations were not observed.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
