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Effects of Alkoxy Chain Length and 1-Hydroxy Group on Anticolorectal Cancer Activity of 2-Bromoalkoxyanthraquinones

Mekzali NW, Chee CW, Abdullah I, Lee YK, Rashid NN, Lee VS, et al.

Med Chem, 2023;19(9):897-905.
PMID: 37046198 DOI: 10.2174/1573406419666230410134213

BACKGROUND: KRAS and p53 are two of the most common genetic alterations associated with colorectal cancer. New drug development targeting these mutated genes in colorectal cancer may serve as a potential treatment avenue to the current regimen.
OBJECTIVE: The objective of the present study was to investigate the effects of alkoxy chain length and 1-hydroxy group on anticolorectal cancer activity of a series of 2-bromoalkoxyanthraquinones and corroborate it with their in silico properties.
METHODS: In vitro anticancer activity of 2-bromoalkoxyanthraquinones was evaluated against HCT116, HT29, and CCD841 CoN cell lines, respectively. Molecular docking was performed to understand the interactions of these compounds with putative p53 and KRAS targets (7B4N and 6P0Z).
RESULTS: 2-Bromoalkoxyanthraquinones with the 1-hydroxy group were proven to be more active than the corresponding counterparts in anticancer activity. Among the tested compounds, compound 6b with a C3 alkoxy chain exhibited the most promising antiproliferation activity against HCT116 cells (IC50 = 3.83 ± 0.05 μM) and showed high selectivity for HCT116 over CCD841 CoN cells (SI = 45.47). The molecular docking reveals additional hydrogen bonds between the 1-hydroxy group of 6b and the proteins. Compound 6b has adequate lipophilicity (cLogP = 3.27) and ligand efficiency metrics (LE = 0.34; LLE = 2.15) close to the proposed acceptable range for an initial hit.
CONCLUSION: This work highlights the potential of the 1-hydroxy group and short alkoxy chain on anticolorectal cancer activity of 2-bromoalkoxyanthraquinones. Further optimisation may be warranted for compound 6b as a therapeutic agent against colorectal cancer.

Matched MeSH terms: Drug Screening Assays, Antitumor
Controlled release of doxorubicin from electrospun PEO/chitosan/graphene oxide nanocomposite nanofibrous scaffolds

Ardeshirzadeh B, Anaraki NA, Irani M, Rad LR, Shamshiri S

Mater Sci Eng C Mater Biol Appl, 2015 Mar;48:384-90.
PMID: 25579938 DOI: 10.1016/j.msec.2014.12.039

Polyethylene oxide (PEO)/chitosan (CS)/graphene oxide (GO) electrospun nanofibrous scaffolds were successfully developed via electrospinning process for controlled release of doxorubicin (DOX). The SEM analysis of nanofibrous scaffolds with different contents of GO (0.1, 0.2, 0.5 and 0.7wt.%) indicated that the minimum diameter of nanofibers was found to be 85nm for PEO/CS/GO 0.5% nanofibers. The π-π stacking interaction between DOX and GO with fine pores of nanofibrous scaffolds exhibited higher drug loading (98%) and controlled release of the DOX loaded PEO/CS/GO nanofibers. The results of DOX release from nanofibrous scaffolds at pH5.3 and 7.4 indicated strong pH dependence. The hydrogen bonding interaction between GO and DOX could be unstable under acidic conditions which resulted in faster drug release rate in pH5.3. The cell viability results indicated that DOX loaded PEO/CS/GO/DOX nanofibrous scaffold could be used as an alternative source of DOX compared with free DOX to avoid the side effects of free DOX. Thus, the prepared nanofibrous scaffold offers as a novel formulation for treatment of lung cancer.

Matched MeSH terms: Drug Screening Assays, Antitumor
Fulltext Cytotoxic aaptamines from Malaysian Aaptos aaptos

Shaari K, Ling KC, Rashid ZM, Jean TP, Abas F, Raof SM, et al.

Mar Drugs, 2009;7(1):1-8.
PMID: 19370166 DOI: 10.3390/md7010001

In a preliminary screen, Aaptos aaptos showed significant cytotoxic activity towards a panel of cell lines and was thus subjected to bioassay-guided isolation of the bioactive constituents. In addition to the known aaptamine, two new derivatives of the alkaloid were isolated from the bioactive chloroform fraction of the crude methanolic extract. Detailed analysis by NMR and mass spectroscopy enabled their identification to be 3-(phenethylamino)demethyl(oxy)aaptamine and 3-(isopentylamino)demethyl(oxy) aaptamine. The cytotoxic activities of the three alkaloids were further evaluated against CEM-SS cells.

Matched MeSH terms: Drug Screening Assays, Antitumor
Secondary B-cell acute lymphoblastic leukemia following Wilms' tumor: clinical and in vitro chemosensitivity studies

Ariffin H, Muthukkumaran T, Stanslas J, Sabariah AR, Veerasekaran N, Lin HP

Leuk Lymphoma, 2005 Aug;46(8):1233-7.
PMID: 16085568

We report the clinical features and in vitro chemosensitivity assay findings of a 13-year-old girl who developed secondary B-cell acute lymphoblastic leukemia (ALL) 7 years after a diagnosis of Wilms' tumor. The patient was treated using the Berlin - Frankfurt - Muenster (BFM) ALL chemotherapy protocol with poor response to initial therapy before succumbing to sepsis. An in vitro chemosensitivity assay on her peripheral blood lymphoblasts was performed while she was undergoing induction therapy and showed a high level of resistance to drugs commonly used for ALL therapy, e.g. steroids, anthracyclines, vincristine and L-asparaginase. The mechanism of chemoresistance was not elicited, but was probably not related to P-glycoprotein (P-gp) over-expression. We believe that the in vitro chemosensitivity assay is a good indicator of cellular response to chemotherapy and may provide reliable information for the basis of the selection of drugs to be used for the treatment of similarly rare patients rather than relying on "standard" protocols.

Matched MeSH terms: Drug Screening Assays, Antitumor
Pharmacological evaluation of poly(3-methylthiophene) and its titanium(IV)phosphate nanocomposite: DNA interaction, molecular docking, and cytotoxic activity

Baig U, Gondal MA, Alam MF, Wani WA, Younus H

J. Photochem. Photobiol. B, Biol., 2016 Nov;164:244-255.
PMID: 27710872 DOI: 10.1016/j.jphotobiol.2016.09.034

Cancer and pathogenic microbial diseases have terribly affected human health over a longer period of time. In response to the increasing casualties due to cancer and microbial diseases, unique poly(3-methylthiophene) and poly(3-methylthiophene)-titanium(IV)phosphate composite were prepared via in-situ oxidative chemical polymerization in this work. The poly(3-methylthiophene) and poly(3-methylthiophene)-titanium(IV)phosphate composite were well characterized by Fourier transform infrared spectroscopy and field emission scanning electron microscopy. DNA binding studies by UV-Visible and fluorescence spectroscopic investigations indicated strong binding affinities of poly(3-methylthiophene) and poly(3-methylthiophene)-titanium(IV)phosphate nanocomposite; leading to structural damage of DNA. Poly(3-methylthiophene)-titanium(IV)phosphate nanocomposite showed stronger interactions with DNA as compared to poly(3-methylthiophene) and from dye displacement assay it was confirmed that mode of binding of both the formulations was intercalative. The antimicrobial screening revealed that polymer and its composite displayed stronger antibacterial effects than ampicillin against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhimurium. Besides, the poly(3-methylthiophene) and poly(3-methylthiophene)-titanium(IV)phosphate nanocomposite showed dose dependent effects towards estrogen receptor positive breast cancer (MCF-7) and estrogen receptor negative breast cancer (MDA-MB-231) cell lines; with poly(3-methylthiophene)-titanium(IV)phosphate nanocomposite showing better activities against both cell lines. In all in-vitro biological investigations, poly(3-methylthiophene)-titanium(IV)phosphate composite showed superior properties to that of the pure poly(3-methylthiophene), which encouraged us to suggest its potential as future therapeutic gear in drug delivery and other allied fields.

Matched MeSH terms: Drug Screening Assays, Antitumor
Fulltext The anti-proliferative effects of a palm oil-derived product and its mode of actions in human malignant melanoma MeWo cells

Komarasamy TV, Sekaran SD

J Oleo Sci, 2012;61(4):227-39.
PMID: 22450124

Melanoma incidence and mortality have risen dramatically in recent years. No effective treatment for metastatic melanoma exists; hence currently, an intense effort for new drug evaluation is being carried out. In this study, we investigated the effects of a palm oil-derived nanopolymer called Bio-12 against human malignant melanoma. The nanopolymers of Bio-12 are lipid esters derived from a range of fatty acids of palm oil. Our study aims to identify the anti-proliferative properties of Bio-12 against human malignant melanoma cell line (MeWo) and to elucidate the mode of actions whereby Bio-12 brings about cell death. Bio-12 significantly inhibited the growth of MeWo cells in a concentration- and time- dependent manner with a median inhibitory concentration (IC₅₀) value of 1/25 dilution after 72 h but was ineffective on human normal skin fibroblasts (CCD-1059sk). We further investigated the mode of actions of Bio-12 on MeWo cells. Cell cycle flow cytometry demonstrated that MeWo cells treated with increasing concentrations of Bio-12 resulted in S-phase arrest, accompanied by the detection of sub-G1 content, indicative of apoptotic cell death. Induction of apoptosis was further confirmed via caspase (substrate) cleavage assay which showed induction of early apoptosis in MeWo cells. In addition, DNA strand breaks which are terminal event in apoptosis were evident through increase of TUNEL positive cells and formation of a characteristic DNA ladder on agarose gel electrophoresis. Moreover, treatment of MeWo cells with Bio-12 induced significant increase in lactate dehydrogenase (LDH) activity. These results show that Bio-12 possesses the ability to suppress proliferation of human malignant melanoma MeWo cells and this suppression is at least partly attributed to the initiation of the S-phase arrest, apoptosis and necrosis, suggesting that it is indeed worth for further investigations.

Matched MeSH terms: Drug Screening Assays, Antitumor
Aspidofractinine and Eburnane Alkaloids from a North Borneo Kopsia. Ring-Contracted, Additional Ring-Fused, and Paucidactine-Type Aspidofractinine Alkaloids from K. pauciflora

Yap WS, Gan CY, Sim KS, Lim SH, Low YY, Kam TS

J Nat Prod, 2016 Jan 22;79(1):230-9.
PMID: 26717050 DOI: 10.1021/acs.jnatprod.5b00992

Eleven new indole alkaloids (1-11) comprising seven aspidofractinine and four eburnane alkaloids, were isolated from the stem-bark extract of Kopsia pauciflora occurring in Malaysian Borneo. The aspidofractinine alkaloids include a ring-contracted, an additional ring-fused, a paucidactine regioisomer, two paucidactine, and one kopsine alkaloid. The structures of several of these alkaloids were also confirmed by X-ray diffraction analyses. The bisindole alkaloids isolated, norpleiomutine and kopsoffinol, showed in vitro growth inhibitory activity against human PC-3, HCT-116, MCF-7, and A549 cells and moderate effects in reversing multidrug-resistance in vincristine-resistant human KB cells.

Matched MeSH terms: Drug Screening Assays, Antitumor
Cytotoxic vobasine, tacaman, and corynanthe-tryptamine bisindole alkaloids from Tabernaemontana and structure revision of tronoharine

Sim DS, Chong KW, Nge CE, Low YY, Sim KS, Kam TS

J Nat Prod, 2014 Nov 26;77(11):2504-12.
PMID: 25333996 DOI: 10.1021/np500589u

Seven new indole alkaloids (1-7) comprising four vobasine, two tacaman, and one corynanthe-tryptamine bisindole alkaloid were isolated from the stem-bark extract of a Malayan Tabernaemontana. Two of the new vobasine alkaloids (1, 3), as well as 16-epivobasine (15) and 16-epivobasenal (17), showed appreciable cytotoxicity toward KB cells (IC50 ca. 5 μg/mL). The structure of the known Tabernaemontana alkaloid tronoharine (8) was revised based on newly acquired NMR data, as well as X-ray diffraction analysis.

Matched MeSH terms: Drug Screening Assays, Antitumor
Rhazinilam-Leuconolam-Leuconoxine Alkaloids from Leuconotis griffithii

Gan CY, Low YY, Thomas NF, Kam TS

J Nat Prod, 2013 May 24;76(5):957-64.
PMID: 23647487 DOI: 10.1021/np400214y

Eight new indole alkaloids (1-8) belonging to the rhazinilam-leuconolam-leuconoxine group, in addition to 52 other alkaloids, were isolated from the stem-bark extract of Leuconotis griffithii, viz., nor-rhazinicine (1), 5,21-dihydrorhazinilam-N-oxide (2), 3,14-dehydroleuconolam (3), and leuconodines A-E (4-8). The structures of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 1, 5, and 7 showed only moderate to weak cytotoxicity toward KB cells (IC50 12-18 μg/mL), while 8 showed moderate activity in reversing MDR in vincristine-resistant KB cells.

Matched MeSH terms: Drug Screening Assays, Antitumor
Grandilodines A-C, biologically active indole alkaloids from Kopsia grandifolia

Yap WS, Gan CY, Low YY, Choo YM, Etoh T, Hayashi M, et al.

J Nat Prod, 2011 May 27;74(5):1309-12.
PMID: 21428274 DOI: 10.1021/np200008g

Three new indole alkaloids (1-3), named grandilodines A-C, and five known ones were obtained from the Malayan Kopsia grandifolia. The structures were established using NMR and MS analyses and, in the case of 1 and 2, were confirmed by X-ray diffraction analyses. Alkaloids 1, 3, and lapidilectine B (8) were found to reverse multidrug resistance in vincristine-resistant KB cells.

Matched MeSH terms: Drug Screening Assays, Antitumor
cis-Clerodane-type furanoditerpenoids from Tinospora crispa

Choudhary MI, Ismail M, Shaari K, Abbaskhan A, Sattar SA, Lajis NH, et al.

J Nat Prod, 2010 Apr 23;73(4):541-7.
PMID: 20356064 DOI: 10.1021/np900551u

Phytochemical and cytotoxicity investigations on organic solvent extracts of the aerial parts of Tinospora crispa have led to the isolation of 15 cis-clerodane-type furanoditerpenoids. Of these, nine compounds (1-9) were found to be new. Spectroscopic assignments of a previously reported compound, borapetoside A (13), were revised on the basis of HMQC and HMBC correlations. No discernible activity was observed when compounds 10-13 were subjected to evaluation in cytotoxicity assays against human prostate cancer (PC-3) and the normal mouse fibroblast (3T3) cell lines.

Matched MeSH terms: Drug Screening Assays, Antitumor
Leucoridines A-D, cytotoxic Strychnos-Strychnos bisindole alkaloids from Leuconotis

Gan CY, Etoh T, Hayashi M, Komiyama K, Kam TS

J Nat Prod, 2010 Jun 25;73(6):1107-11.
PMID: 20515042 DOI: 10.1021/np1001187

Four new bisindole alkaloids of the Strychnos-Strychnos type, leucoridines A-D (1-4), were isolated from the stem-bark extract of Leuconotis griffithii. Alkaloids 1-4 showed moderate cytotoxicity against drug-sensitive and vincristine-resistant human KB cells.

Matched MeSH terms: Drug Screening Assays, Antitumor
Rearranged diterpenoids from the biotransformation of ent-trachyloban-18-oic acid by Rhizopus arrhizus

Leverrier A, Martin MT, Servy C, Ouazzani J, Retailleau P, Awang K, et al.

J Nat Prod, 2010 Jun 25;73(6):1121-5.
PMID: 20481544 DOI: 10.1021/np100145n

In our search for inhibitors of the antiapoptotic protein Bcl-xL, investigation of Xylopia caudata afforded a new diterpenoid, ent-trachyloban-4beta-ol (2), and five known ent-trachylobane or ent-atisane compounds. Only ent-trachyloban-18-oic acid (1) exhibited weak binding activity to Bcl-xL. These compounds exhibited cytotoxicity against KB and HCT-116 cell lines with IC(50) values between 10 and 30 microM. Bioconversion of compound 1 by Rhizopus arrhizus afforded new hydroxylated metabolites (3-7) of the ent-trachylobane and ent-kaurene type and compound 8, with a rearranged pentacyclic carbon framework that was named rhizopene. Compounds 3-8 were noncytotoxic to the two cancer cell lines, and compounds 3 and 5 exhibited only weak binding affinity for Bcl-xL.

Matched MeSH terms: Drug Screening Assays, Antitumor
Chrotacumines A-D, chromone alkaloids from Dysoxylum acutangulum

Ismail IS, Nagakura Y, Hirasawa Y, Hosoya T, Lazim MI, Lajis NH, et al.

J Nat Prod, 2009 Oct;72(10):1879-83.
PMID: 19757855 DOI: 10.1021/np9003849

Four new chromone alkaloids, chrotacumines A-D (1-4), consisting of a 5,7-dihydroxy-2-methylchromone, an N-Me piperidine ring, and an ester side chain were isolated from Dysoxylum acutangulum, and their structures including absolute configurations were elucidated on the basis of spectroscopic data interpretation including 2D NMR, CD spectra, and X-ray analysis. The known compound rohitukine (5) showed moderate cytotoxicity against human HL-60 promyelocytic leukemia and HCT-116 colon cancer cells.

Matched MeSH terms: Drug Screening Assays, Antitumor
Leuconicines A-G and (-)-eburnamaline, biologically active strychnan and eburnan alkaloids from Leuconotis

Gan CY, Low YY, Etoh T, Hayashi M, Komiyama K, Kam TS

J Nat Prod, 2009 Dec;72(12):2098-103.
PMID: 20035556 DOI: 10.1021/np900576b

Seven new indole alkaloids of the Strychnos type, leuconicines A-G (1-7), and a new eburnan alkaloid, (-)-eburnamaline (8), were isolated from the stem-bark extract of two Malayan Leuconotis species. The structures of these alkaloids were established using NMR and MS analysis and in the case of 8 also by partial synthesis. Alkaloids 1-5 reversed multidrug resistance in vincristine-resistant KB cells.

Matched MeSH terms: Drug Screening Assays, Antitumor
Bisnicalaterine A, a vobasine-vobasine bisindole alkaloid from Hunteria zeylanica

Nugroho AE, Hirasawa Y, Kawahara N, Goda Y, Awang K, Hadi AH, et al.

J Nat Prod, 2009 Aug;72(8):1502-6.
PMID: 19388660 DOI: 10.1021/np900115q

A new bisindole alkaloid, bisnicalaterine A (1), consisting of two vobasine-type skeletons, and 3-epivobasinol (2) and 3-O-methylepivobasinol (3), with vobasine-type skeletons, were isolated from the leaves of Hunteria zeylanica, and their structures were elucidated on the basis of spectroscopic data and chemical correlation. Bisnicalaterine A showed moderate cytotoxicity against various human cancer cell lines.

Matched MeSH terms: Drug Screening Assays, Antitumor
A cycloartane incorporating a fused tetrahydrofuran ring and a cytotoxic lactam from Monocarpia marginalis

Lim SH, Mahmood K, Komiyama K, Kam TS

J Nat Prod, 2008 Jun;71(6):1104-6.
PMID: 18462006 DOI: 10.1021/np800123g

A new cycloartane, monocarpinine (1), incorporating a fused tetrahydrofuranyl ring, and a cytotoxic tetracyclic lactam, monomarginine (2), were isolated from a stem bark extract of the Malayan species Monocarpia marginalis. The structures of these compounds were determined using NMR and MS analysis. Monomarginine (2) showed appreciable cytotoxicity toward human KB (both drug-sensitive and drug-resistant) and Jurkat cells.

Matched MeSH terms: Drug Screening Assays, Antitumor
Inhibitors of the NF-kappaB activation pathway from Cryptocarya rugulosa

Meragelman TL, Scudiero DA, Davis RE, Staudt LM, McCloud TG, Cardellina JH, et al.

J Nat Prod, 2009 Mar 27;72(3):336-9.
PMID: 19093800 DOI: 10.1021/np800350x

The nuclear factor-kappaB (NF-kappaB) signaling pathway is constitutively active in many types of cancers and is a potential therapeutic target. Using a cell-based assay for stability of inhibitor of kappa B (IkappaB), a critical regulator of NF-kappaB activity, we found that an organic solvent extract of the plant Cryptocarya rugulosa inhibited constitutive NF-kappaB activity in human lymphoma cell lines. The active components were identified as rugulactone, a new alpha-pyrone (1), and the known cryptocaryone (2). Rugulactone was the more active compound, exhibiting up to 5-fold induction of IkappaB at 25 microg/mL; maximal activity was observed with 10 h exposure of test cells to 1 or 2.

Matched MeSH terms: Drug Screening Assays, Antitumor
Jerantinines A-G, cytotoxic Aspidosperma alkaloids from Tabernaemontana corymbosa

Lim KH, Hiraku O, Komiyama K, Kam TS

J Nat Prod, 2008 Sep;71(9):1591-4.
PMID: 18778099 DOI: 10.1021/np800435c

Seven new indole alkaloids of the Aspidosperma type, jerantinines A-G (1-7), were isolated from a leaf extract of the Malayan Tabernaemontana corymbosa. The structures were established using NMR and MS analysis. Five of the alkaloids isolated and two derivatives (1-5, 8, 9) displayed pronounced in vitro cytotoxicity against human KB cells (IC50 < 1 microg/mL).

Matched MeSH terms: Drug Screening Assays, Antitumor
Biologically active aspidofractinine alkaloids from Kopsia singapurensis

Subramaniam G, Hiraku O, Hayashi M, Koyano T, Komiyama K, Kam TS

J Nat Prod, 2008 Jan;71(1):53-7.
PMID: 18078327

Ten new indole alkaloids of the aspidofractinine type, in addition to several recently reported indole alkaloids and 20 other known alkaloids, were obtained from the leaf and stem-bark extract of the Malayan Kopsia singapurensis, viz., kopsimalines A-E (1-5), kopsinicine (6), kopsofinone (7), and kopsiloscines H-J (8-10). The structures of these alkaloids were determined using NMR and MS analysis. Kopsimalines A (1), B (2), C (3), D (4), and E (5) and kopsiloscine J (10) were found to reverse multidrug-resistance in vincristine-resistant KB cells, with 1 showing the highest potency.

Matched MeSH terms: Drug Screening Assays, Antitumor

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