81677-50-1Relevant academic research and scientific papers
Discovery and preliminary mechanism of 1-carbamoyl β-carbolines as new antifungal candidates
Sheng, Tao,Kong, Mengmeng,Wang, Yujie,Wu, HuiJun,Gu, Qin,Chuang, Anita Shyying,Li, Shengkun,Gao, Xuewen
, (2021/06/21)
Natural β-carboline alkaloids are ideal models for the discovery of pharmaceutically important entities. Various 1-substituted β-carbolines were synthesized from commercially inexpensive tryptophan and demonstrated significant in vitro antifungal activity against G. graminis. Significantly, compound 4m (EC50 = 0.45 μM) with carboxamide at 1-position displayed the best efficacy and nearly 20 folds enhancement in antifungal potential compared to Silthiopham (EC50 = 8.95 μM). Moreover, compounds 6, 7, and 4i exhibited excellent in vitro antifungal activities and in vivo protective and curative activities against B. cinerea and F. graminearum. Preliminary mechanism studies revealed that compound 4m caused reactive oxygen species accumulation, cell membrane destruction, and deregulation of histone acetylation. These findings indicated that 1-carbamoyl β-carboline can be selected as a promising model for the discovery of novel and broad-spectrum fungicide candidates.
Development of β-carboline-benzothiazole hybrids via carboxamide formation as cytotoxic agents: DNA intercalative topoisomerase IIα inhibition and apoptosis induction
Tokala, Ramya,Mahajan, Surbhi,Kiranmai, Gaddam,Sigalapalli, Dilep Kumar,Sana, Sravani,John, Stephy Elza,Nagesh, Narayana,Shankaraiah, Nagula
, (2020/12/07)
In quest of promising anticancer agents, the pharmacophores of natural (β-carboline) and synthetic origin (benzothiazole) were adjoined by a carboxamide bridge and three-point diversification was accomplished. The in vitro cytotoxic ability of the compounds was established on adherent and suspension human cancer cell lines and compounds 8u and 8f advanced as pre-eminent molecules with IC50 values of 1.46 and 1.81 μM respectively in A549 cell line. The cytospecificity was entrenched for potent compounds 8u and 8f by evaluating against normal human lung epithelial cells and selectivity index was calculated. Furthermore, EtBr displacement, relative viscosity and gel-based topoisomerase II target assays unveiled the intercalative topo-II inhibitory capability and DNA binding studies (absorbance) revealed the dissociation constant (Kd) for compounds 8u and 8f as 98 and 103 μM respectively. Additionally, cell-based flow cytometric assays like Annexin-V/PI dual staining aids in the quantification of apoptosis induced and JC-1 staining disclosed the depolarization of mitochondrial membrane potential by compound 8u in A549 cells in a dose-dependent manner. Moreover, wound healing assay established the inhibition of in vitro cell migration by compound 8u on A549 cells. In addition, molecular docking studies proved the binding of compounds 8u and 8f in the active site of DNA complexed with topo IIα and stabilized by interactions with DNA base pairs and amino acid residues. Remarkably, the compounds 8u and 8f follow Lipinski's rule of five and are in the recommended range for Jorgensen's rule of three with a minimal violation and other pharmacokinetic parameters revealing druggability of the synthesized hybrids.
Diastereospecific Synthesis of Tetrahydroisoquinolines via Radical Cyclization: Application in the Synthesis of ent-Tadalafil
Barve, Indrajeet J.,Chiu, Wei-Jung,Lin, Yan-Liang,Sun, Chung-Ming
supporting information, p. 4041 - 4046 (2021/07/10)
An enantioselective synthesis of 1-substituted tetrahydroisoquinolines from L–Dopa methyl ester through intramolecular aryl radical cyclization is demonstrated. The strategy consists of bromination of (S)-2-amino-3-(2-bromo-4,5-dimethoxyphenyl)propanoate followed by condensation with various aldehydes to afford bromoimidate ester. Aryl radicals generated from bromoimidate ester under the radical generating conditions (nBu3SnH/AIBN) cyclizes via 6-endo mode to afford cis-1-substituted tetrahydroisoquinolines exclusively in 99% ee. The utility of this synthetic protocol is demonstrated in the synthesis of (6S, 12aS) Tadalafil (5 steps, 21%, 99% ee). (Figure presented.).
β-Carboline tethered cinnamoyl 2-aminobenzamides as class I selective HDAC inhibitors: Design, synthesis, biological activities and modelling studies
Godugu, Chandraiah,Kamal, ahmed,Lakshmi Manasa, Kesari,Namballa, Hari Krishna,Shankaraiah, Nagula,Soni, Jay Prakash,anchi, Pratibha
, (2021/11/11)
The effect of β-carboline motif as cap for HDAC inhibitors containing cinnamic acid as linker and benzamides as zinc binding group was examined in this study. A series of β-carboline-cinnamide conjugates have been synthesized and evaluated for their HDAC inhibitory activity and in vitro cytotoxicity against different human cancer cell lines. Almost all the compounds exhibited superior HDAC inhibitory activity than the standard drug Entinostat for in vitro enzymatic assay. Among the tested compounds, 7h displayed a noteworthy potency with an IC50 value of 0.70 ± 0.15 μM against HCT-15 cell line when compared to the standard drug Entinostat (IC50 of 3.87 ± 0.62 μM). The traditional apoptosis assays such as nuclear morphological alterations, AO/EB, DAPI, and Annexin-V/PI staining revealed the antiproliferative activity of 7h while depolarization of mitochondrial membrane potential by JC-1 was observed in dose-dependent manner. Cell cycle analysis also unveiled the typical accumulation of cells in G2M phase and sub-G1/S phase arrest. In addition, immunoblot analysis for compound 7h on HCT-15 indicated selective inhibition of the protein expression of class I HDAC 2 and 3 isoforms. Molecular docking analysis of compound 7h revealed that it can prominent binding with the active pocket of the HDAC 2. These finding suggest that the compound 7h can be a promising lead candidate for further investigation in the development of novel anti-cancer drug potentially inhibiting HDACs.
Selective construction of alkaloid scaffolds by alcohol-based direct and mild aerobic oxidative Pictet-Spengler reactions
Han, Feng,Li, Huan,Liu, Haicheng,Liu, Jianping,Xu, Qing
supporting information, p. 7079 - 7085 (2020/10/02)
Employing TBN/TEMPO as the catalysts and oxygen as the oxidant, the biologically and pharmaceutically significant tetrahydro-β-carboline and β-carboline alkaloid scaffolds that used to be obtained by multi-step processes can now be selectively obtained in only one-stepviadirect aerobic oxidative Pictet-Spengler reactions of tryptamines with alcohols under mild conditions, with water generated as the byproduct. In this reaction, TBN/TEMPO was interestingly found to be able to facilitate the cyclization step of the whole reaction. This method tolerates a variety ofC- andN-substituted tryptamines, and both the more reactive benzylic and allylic alcohols and the less reactive aliphatic alcohols. This method can also be extended to dihydro-β-carboline synthesis and applied to the more available and more economical tryptophan for β-carboline synthesis, revealing its broad substrate scope and potential in synthetic applications.
Design and synthesis of β-carboline linked aryl sulfonyl piperazine derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability
Alvala, Mallika,Godugu, Chandraiah,Kalle, Arunasree M.,Kiranmai, Gaddam,Lakshmi Manasa, Kesari,Nagendra Babu, Bathini,Nagesh, Narayana,Sagar, Arpita,Sigalapalli, Dilep Kumar,Thatikonda, Sowjanya
, (2020/07/20)
A series of new β-carboline linked aryl sulfonyl piperazine congeners have been synthesized by coupling various β-carboline acids with substituted aryl sulfonyl piperazines. Evaluation of their anticancer activity against a panel of human cancer cell lines such as colon (HT-29), breast (MDA-MB-231), bone osteosarcoma (MG-63), brain (U87 MG), prostate (PC- 3) and normal monkey kidney (Vero) cell line has been done. Among the series, compound 8ec and 8ed has shown most potent cytotoxicity with an IC50 values of 2.80 ± 0.10 μM and 0.59 ± 0.28 μM respectively against MG-63 cell line and also potent on other cell lines tested. Compounds 8ec and 8ed was found to inhibit Topo II that is confirmed by specific Topo II inhibition assay. DNA binding studies, cell cycle analysis, Annexin V study indicate that these compounds has potential anticancer activity. Molecular docking studies for compound 8ec and 8ed are incorporated to understand the nature of interaction with topoisomerase IIα and dsDNA.
Design and synthesis of thiadiazolo-carboxamide bridged β-carboline-indole hybrids: DNA intercalative topo-IIα inhibition with promising antiproliferative activity
Tokala, Ramya,Sana, Sravani,Lakshmi, Uppu Jaya,Sankarana, Prasanthi,Sigalapalli, Dilep Kumar,Gadewal, Nikhil,Kode, Jyoti,Shankaraiah, Nagula
, (2020/10/27)
The conjoining of salient pharmacophoric properties directing the development of prominent cytotoxic agents was executed by constructing thiadiazolo-carboxamide bridged β-carboline-indole hybrids. On the evaluation of in vitro cytotoxic potential, 12c exhibited prodigious cytotoxicity among the synthesized new molecules 12a–k, with an IC50 50 value of 2.82 ± 0.10 μM. Besides, another compound 12a also displayed impressive cytotoxicity against A549 cell line (IC50: 3.00 ± 1.40 μM). Further target-based assay of these two compounds 12c and 12a revealed their potential as DNA intercalative topoisomerase-IIα inhibitors. Additionally, the antiproliferative activity of compound 12c was measured in A549 cells by traditional apoptosis assays revealing the nuclear, morphological alterations, and depolarization of membrane potential in mitochondria and externalization of phosphatidylserine in a concentration-dependent manner. Cell cycle analysis unveiled the G0/G1 phase inhibition and wound healing assay inferred the inhibition of in vitro cell migration by compound 12c in lung cancer cells. Remarkably, the safety profile of compound 12c was disclosed by screening against normal human lung epithelial cell line (BEAS-2B: IC50: 71.2 ± 7.95 μM) with a selectivity index range of 14.9–25.26. Moreover, Molecular modeling studies affirm the intercalative binding of compound 12c and 12a in the active pocket of topo-IIα. Furthermore, in silico prediction of physico-chemical parameters divulged the propitious drug-like properties of the synthesized derivatives.
1-substituted beta-carboline derivative and application thereof
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Paragraph 0039; 0096-0098; 0111-0113, (2020/07/13)
The invention discloses 1-substituted beta-carboline derivatives and an application of the 1-substituted beta-carboline derivatives. According to the invention, beta-carboline is used as a parent nucleus; the 1-substituted beta-carboline derivatives are mainly synthesized by introducing alkyl and electron withdrawing groups at the No.1 position, agriculturally important plant pathogenic fungi andbacteria are selected, the inhibitory activity of the compound on fungi and bacteria is tested, and bacteriostatic activity test results show that the 1-substituted beta-carboline derivatives have inhibitory activity on various plant pathogenic bacteria.
Bimetallic catalyzed N-arylation used in synthesis of novel β-carbolines derivatives
Cai, Rui,Wang, Pengfei,Zhao, Yu,Zhu, Li
, p. 520 - 525 (2020/04/17)
Background: Natural occurring β-Carbolines alkaloids are abundant in the plant king-dom or other organisms, and they were found to possess good antitumor activity through multiple mechanisms. Based on previous summarized SARs of β-carboline derivatives, t
Synthesis, Antileishmanial Activity and Spin Labeling EPR Studies of Novel β-Carboline-Oxazoline and β-Carboline-Dihydrooxazine Derivatives
Alonso, Antonio,Alonso, Laís,Baréa, Paula,Nakamura, Celso V.,Sarragiotto, Maria H.,da Costa, Willian F.,de Oliveira, Aline R.,de Paula, Jéssica C.
, p. 1170 - 1185 (2020/10/14)
A series of novel 1-(substituted-phenyl)-3-(4,5-dihydro-1,3-oxazol-2-yl)-9H-β-carboline (8a-8i) and 1-(substituted-phenyl)-3-(5,6-dihydro-4H-1,3-oxazin-2-yl)-9H-β-carboline (9a-9h) derivatives, as well as their respective N-(chloroalkyl)-1-(substituted-phenyl)-9H-β-carboline-3-carboxamide precursors (6a-6i and 7a-7h), were synthesized and evaluated for their in vitro antileishmanial activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. Compounds 8d, 8i, 9e and 9h exhibited significant activity for both promastigote and amastigote forms, with IC50 (50% inhibitory concentration) values ranging from 2.9 to 23.0 μM. In addition, spin label electron paramagnetic resonance (EPR) spectroscopy studies were carried out for the most active compounds against L. amazonensis promastigotes. The studies indicated that the tested compounds cause strong stiffness in the parasite plasma membrane and are capable of inducing internal metalloproteins oxidation of the parasite, resulting in their cross-linking to skeletal proteins. Compounds 8d and 8i produced the largest effect, showing that the presence of oxazoline group at C-3 of β-carboline nucleus is important for antileishmanial activity.
