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Correction to "Apoferritin-Encapsulated Jerantinine A for Transferrin Receptor Targeting and Enhanced Selectivity in Breast Cancer Therapy"

Abuzaid H, Abdelrazig S, Ferreira L, Collins HM, Kim DH, Lim KH, et al.

ACS Omega, 2024 Jan 09;9(1):2012.

PMID: 38222495 DOI: 10.1021/acsomega.3c09291

[This corrects the article DOI: 10.1021/acsomega.2c00997.].

Fulltext Apoferritin-Encapsulated Jerantinine A for Transferrin Receptor Targeting and Enhanced Selectivity in Breast Cancer Therapy

Abuzaid H, Abdelrazig S, Ferreira L, Collins HM, Kim DH, Lim KH, et al.

ACS Omega, 2022 Jun 28;7(25):21473-21482.

PMID: 35785302 DOI: 10.1021/acsomega.2c00997

The O-acetyl (or acetate) derivative of the Aspidosperma alkaloid Jerantinine A (JAa) elicits anti-tumor activity against cancer cell lines including mammary carcinoma cell lines irrespective of receptor status (0.14 < GI50 < 0.38 μM), targeting microtubule dynamics. By exploiting breast cancer cells' upregulated transferrin receptor 1 (TfR1) expression and apoferritin (AFt) recognition, we sought to develop an AFt JAa-delivery vehicle to enhance tumor-targeting and reduce systemic toxicity. Optimizing pH-mediated reassembly, ∼120 JAa molecules were entrapped within AFt. Western blot and flow cytometry demonstrate TfR1 expression in cancer cells. Enhanced internalization of 5-carboxyfluorescein-conjugated human AFt in SKBR3 and MDA-MB-231 cancer cells is observed compared to MRC5 fibroblasts. Accordingly, AFt-JAa delivers significantly greater intracellular JAa levels to SKBR3 and MDA-MB-231 cells than naked JAa (0.2 μM) treatment alone. Compared to naked JAa (0.2 μM), AFt-JAa achieves enhanced growth inhibition (2.5-14-fold; <0.02 μM < GI50 < 0.15 μM) in breast cancer cells; AFt-JAa treatment results in significantly reduced clonal survival, more profound cell cycle perturbation including G2/M arrest, greater reduction in cell numbers, and increased apoptosis compared to the naked agent (p < 0.01). Decreased PLK1 and Mcl-1 expression, together with the appearance of cleaved poly (ADP-ribose)-polymerase, corroborate the augmented potency of AFt-JAa. Hence, we demonstrate that AFt represents a biocompatible vehicle for targeted delivery of JAa, offering potential to minimize toxicity and enhance JAa activity in TfR1-expressing tumors.

Divergent Synthesis of Skeletally Distinct Arboridinine and Arborisidine

Wang C, Pang Y, Wu Y, Zhang N, Yang R, Li Y, et al.

Angew Chem Int Ed Engl, 2021 12 20;60(52):26978-26985.

PMID: 34665909 DOI: 10.1002/anie.202110149

A divergent synthesis of skeletally distinct arboridinine and arborisidine was achieved. The central divergent strategy was inspired by the divergent biosynthetic cyclization mode of arboridinine and arborisidine and their hidden topological connection. The branch point was reached through a Michael and Mannich cascade process. A site-selective intramolecular Mannich reaction was developed to construct the tetracyclic core of arboridinine, while a site-selective intramolecular α-amination of ketone was used to access the tetracyclic core of arborisidine. A strategic Peterson olefination through intramolecular nucleophile delivery was able to set up the exocyclic olefin of arboridinine.

Asymmetric Synthesis of Arboduridine

Yang R, Zhou Z, Jiang H, Kam TS, Chen K, Ma Z

Angew Chem Int Ed Engl, 2024 Jan 15;63(3):e202316016.

PMID: 38038685 DOI: 10.1002/anie.202316016

The first asymmetric total synthesis of the monoterpenoid indole alkaloid arboduridine has been accomplished. The tricyclic A/B/D ring system was constructed by an enantioselective Michael reaction followed by intramolecular nucleophilic addition. Intramolecular α-amination of a ketone forged the piperidine ring, while a Horner-Wadsworth-Emmons (HWE) reaction was used to form the pyrrolidine ring. A reduction cyclization cascade led to formation of the tetrahydrofuran ring.

Fulltext The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun

Alhuthali HM, Bradshaw TD, Lim KH, Kam TS, Seedhouse CH

BMC Cancer, 2020 Jul 07;20(1):629.

PMID: 32635894 DOI: 10.1186/s12885-020-07119-2

BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous hematological malignancy with poor long-term survival. New drugs which improve the outcome of AML patients are urgently required. In this work, the activity and mechanism of action of the cytotoxic indole alkaloid Jerantinine B (JB), was examined in AML cells.

METHODS: We used a combination of proliferation and apoptosis assays to assess the effect of JB on AML cell lines and patient samples, with BH3 profiling being performed to identify early effects of the drug (4 h). Phosphokinase arrays were adopted to identify potential driver proteins in the cellular response to JB, the results of which were confirmed and extended using western blotting and inhibitor assays and measuring levels of reactive oxygen species.

RESULTS: AML cell growth was significantly impaired following JB exposure in a dose-dependent manner; potent colony inhibition of primary patient cells was also observed. An apoptotic mode of death was demonstrated using Annexin V and upregulation of apoptotic biomarkers (active caspase 3 and cleaved PARP). Using BH3 profiling, JB was shown to prime cells to apoptosis at an early time point (4 h) and phospho-kinase arrays demonstrated this to be associated with a strong upregulation and activation of both total and phosphorylated c-Jun (S63). The mechanism of c-Jun activation was probed and significant induction of reactive oxygen species (ROS) was demonstrated which resulted in an increase in the DNA damage response marker γH2AX. This was further verified by the loss of JB-induced C-Jun activation and maintenance of cell viability when using the ROS scavenger N-acetyl-L-cysteine (NAC).

CONCLUSIONS: This work provides the first evidence of cytotoxicity of JB against AML cells and identifies ROS-induced c-Jun activation as the major mechanism of action.

Cytotoxic effects and reversal of multidrug resistance by ibogan and related indole alkaloids

Kam TS, Sim KM, Pang HS, Koyano T, Hayashi M, Komiyama K

Bioorg Med Chem Lett, 2004 Sep 6;14(17):4487-9.

PMID: 15357977

A series of indole alkaloids of the ibogan-type was assessed for their cytotoxic effects as well as their potential in reversing MDR in vincristine-resistant KB cells. Of a total of 25 compounds tested, 3(S)-cyanocoronaridine, 3(S)-cyanoisovoacangine, 3(S)-cyanovoacangine, and 10,11-demethoxychippiine were found to show appreciable cytotoxicity toward KB cells, while coronaridine, heyneanine, 19-epi-heyneanine, dippinine B, and dippinine C, were found to reverse MDR in vincristine-resistant KB cells.

Reversal of multidrug resistance (MDR) by aspidofractinine-type indole alkaloids

Kam TS, Subramaniam G, Sim KM, Yoganathan K, Koyano T, Toyoshima M, et al.

Bioorg Med Chem Lett, 1998 Oct 06;8(19):2769-72.

PMID: 9873619

A series of indole alkaloids of the aspidofractinine-type was assessed for their potential in reversing MDR in vincristine-resistant KB cells. Of the compounds tested, kopsiflorine, kopsamine, pleiocarpine, 11-methoxykopsilongine, lahadinine A and N-methoxycarbonyl-11,12-methylenedioxy-delta 16,17-kopsinine were found to show appreciable activity.

Conodiparines A-D, new bisindoles from Tabernaemontana. Reversal of vincristine-resistance with cultured cells

Kam TS, Sim KM, Koyano T, Toyoshima M, Hayashi M, Komiyama K

Bioorg Med Chem Lett, 1998 Jul 07;8(13):1693-6.

PMID: 9873417

Four new bisindoles of the vobasine-iboga type, conodiparines A-D were obtained from Tabernaemontana corymbosa which showed appreciable activity in reversing resistance in vincristine-resistant KB cells.

In vitro anticancer properties and biological evaluation of novel natural alkaloid jerantinine B

Qazzaz ME, Raja VJ, Lim KH, Kam TS, Lee JB, Gershkovich P, et al.

Cancer Lett, 2016 Jan 28;370(2):185-97.

PMID: 26515390 DOI: 10.1016/j.canlet.2015.10.013

Natural products play a pivotal role in medicine especially in the cancer arena. Many drugs that are currently used in cancer chemotherapy originated from or were inspired by nature. Jerantinine B (JB) is one of seven novel Aspidosperma indole alkaloids isolated from the leaf extract of Tabernaemontana corymbosa. Preliminary antiproliferative assays revealed that JB and JB acetate significantly inhibited growth and colony formation, accompanied by time- and dose-dependent apoptosis induction in human cancer cell lines. JB significantly arrested cells at the G2/M cell cycle phase, potently inhibiting tubulin polymerisation. Polo-like kinase 1 (PLK1; an early trigger for the G2/M transition) was also dose-dependently inhibited by JB (IC50 1.5 µM). Furthermore, JB provoked significant increases in reactive oxygen species (ROS). Annexin V+ cell populations, dose-dependent accumulation of cleaved-PARP and caspase 3/7 activation, and reduced Bcl-2 and Mcl-1 expression confirm apoptosis induction. Preclinical in silico biopharmaceutical assessment of JB calculated rapid absorption and bioavailability >70%. Doses of 8-16 mg/kg JB were predicted to maintain unbound plasma concentrations >GI50 values in mice during efficacy studies. These findings advocate continued development of JB as a potential chemotherapeutic agent.

Biologically active ibogan and vallesamine derivatives from Tabernaemontana divaricata

Kam TS, Pang HS, Choo YM, Komiyama K

Chem Biodivers, 2004 Apr;1(4):646-56.

PMID: 17191876

Six new indole alkaloids, viz., (3S)-3-cyanocoronaridine (2), (3S)-3-cyanoisovoacangine (3), conolobine A (5), conolobine B (6), conolidine (7), and (3R/3S)-3-ethoxyvoacangine (8), in addition to 36 known ones, were obtained from the stem-bark extract of the Malayan Tabernaemontana divaricata. The structures were determined by NMR and MS analysis. The CN-substituted alkaloids showed appreciable cytotoxicity towards the KB human oral epidermoid carcinoma cell-line.

Transformations of Ferric Chloride-Generated Stilbene Cation Radicals. The Effect of Aromatic Substitution and a Comparison with Anodic Oxidation

Hong FJ, Chong KW, Low YY, Thomas NF, Kam TS

Chem Asian J, 2015 Oct;10(10):2207-20.

PMID: 26097065 DOI: 10.1002/asia.201500488

A systematic study on the FeCl3-induced oxidation of 1,2-diarylalkenes was carried out with the focus on the variation of product type as a function of aromatic substitution, as well as to compare the reactivity of stilbene cation radicals generated via Fe(III) oxidation with those generated by anodic oxidation. The aromatic substituents were found to fall into three main categories, namely those that give rise to tetralins and/or dehydrotetralins, those that give products possessing pallidol and ampelopsin F-type carbon skeletons, and last, those that give rise to trimeric products, indanes, and dehydrotetralins/tetralins. The latter are those stilbenes with a para-methoxy substituent in one ring and a para- or meta-EWG (CF3, NO2, Cl, F) in the other, and represent the most prominent departure when compared with the behavior of the same stilbenes under the conditions of anodic oxidation. Reaction pathways to rationalize the formation of the different products are presented.

Synergistic cytotoxic effects of combined δ-tocotrienol and jerantinine B on human brain and colon cancers

Abubakar IB, Lim KH, Kam TS, Loh HS

J Ethnopharmacol, 2016 May 26;184:107-18.

PMID: 26947901 DOI: 10.1016/j.jep.2016.03.004

The genus Tabernaemontana has widespread distribution throughout tropical and subtropical parts of the world, i.e. Africa, Asia and America which has long been used for treatments of different disease conditions including tumours, wounds, syphilis, stomach ache and headache. Some Tabernaemontana species are used for treatment of piles, spleen and abdominal tumours in India. In particular, the leaf of Tabernaemontana corymbosa is used for treatment of tumours in Bangladesh. Parts of the plant or whole plants are used as decoctions, steam bath, powder and ointments.

Cardiovascular responses in the normotensive rat produced by intravenous injection of gambirine isolated from Uncaria callophylla B1. ex Korth

Mok JS, Chang P, Lee KH, Kam TS, Goh SH

J Ethnopharmacol, 1992 Jun;36(3):219-23.

PMID: 1434680

Among several alkaloids, including dimeric indoles, isolated from Uncaria callophylla, gambirine which is an alkaloid unique to this plant, has been found to be another hypotensive principle from the plant. Intravenous injections of gambirine in the dose range of 0.2 to 10.0 mg/kg caused a dose-related fall in both systolic and diastolic blood pressures as well as heart rate. At all doses gambirine showed a prompt onset of action and at the higher doses (5.0-10 mg/kg), marked persistence of hypotension accompanied by severe bradycardia were observed. In addition, higher doses of gambirine produced a more marked decrease in diastolic than systolic pressure while at lower doses both decreased equally. It is suggested that the hypotensive effect of gambirine may be peripheral in origin and is associated, at least in part, with a cardiac action.

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.

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.

Oxidized derivatives of macroline, sarpagine, and pleiocarpamine alkaloids from Alstonia angustifolia

Tan SJ, Lim JL, Low YY, Sim KS, Lim SH, Kam TS

J Nat Prod, 2014 Sep 26;77(9):2068-80.

PMID: 25211145 DOI: 10.1021/np500439u

A total of 20 new indole alkaloids comprising mainly oxidized derivatives of macroline- (including alstofonidine, a macroline indole incorporating a butyrolactone ring-F), pleiocarpamine-, and sarpagine-type alkaloids were isolated from the bark and leaf extracts of Alstonia angustifolia. The structures and relative configurations of these alkaloids were determined using NMR and MS analyses and in some instances confirmed by X-ray diffraction analyses. Alkaloids 3, 7, 35, and 41 showed moderate to weak activity, while 21 showed strong activity in reversing multidrug resistance in vincristine-resistant KB cells.

Andransinine: an unusual case of spontaneous resolution in an indole alkaloid derivative

Low YY, Gan CY, Kam TS

J Nat Prod, 2014 Jun 27;77(6):1532-5.

PMID: 24832351 DOI: 10.1021/np500289t

Racemic andransinine (1), an indole alkaloid derivative obtained during isolation of alkaloids from Alstonia angustiloba and Kopsia pauciflora, was found to undergo spontaneous resolution when crystallized in EtOAc, forming racemic conglomerates (an equimolar mechanical mixture of enantiomerically pure individual crystals). X-ray analyses of the enantiomers (obtained from crystals from EtOAc solution and from chiral-phase HPLC) provided the absolute configuration of each enantiomer as (15R,16S,21R)-(+)-andransinine (1a or I+) and (15S,16R,21S)-(-)-andransinine (1b or I-).

Transformations of the 2,7-Seco Aspidosperma alkaloid leuconolam, structure revision of epi-leuconolam, and partial syntheses of leuconoxine and leuconodines A and F

Low YY, Hong FJ, Lim KH, Thomas NF, Kam TS

J Nat Prod, 2014 Feb 28;77(2):327-38.

PMID: 24428198 DOI: 10.1021/np400922x

Several transformations of the seco Aspidosperma alkaloid leuconolam were carried out. The based-induced reaction resulted in cyclization to yield two epimers, the major product corresponding to the optical antipode of a (+)-meloscine derivative. The structures and relative configuration of the products were confirmed by X-ray diffraction analysis. Reaction of leuconolam and epi-leuconolam with various acids, molecular bromine, and hydrogen gave results that indicated that the structure of the alkaloid, previously assigned as epi-leuconolam, was incorrect. This was confirmed by an X-ray diffraction analysis, which revealed that epi-leuconolam is in fact 6,7-dehydroleuconoxine. Short partial syntheses of the diazaspiro indole alkaloid leuconoxine and the new leuconoxine-type alkaloids leuconodines A and F were carried out.

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.

Perhentidines A-C: macroline-macroline bisindoles from Alstonia and the absolute configuration of perhentinine and macralstonine

Lim SH, Low YY, Tan SJ, Lim KH, Thomas NF, Kam TS

J Nat Prod, 2012 May 25;75(5):942-50.

PMID: 22559995 DOI: 10.1021/np300120p

Three new bisindole alkaloids of the macroline-macroline type, perhentidines A-C (1-3), were isolated from the stem-bark extract of Alstonia macrophylla and Alstonia angustifolia. The structures of these alkaloids were established on the basis of NMR and MS analyses. The absolute configurations of perhentinine (4) and macralstonine (5) were established by X-ray diffraction analyses, which facilitated assignment of the configuration at C-20 in the regioisomeric bisindole alkaloids perhentidines A-C (1-3). A potentially useful method for the determination of the configuration at C-20 based on comparison of the NMR chemical shifts of the bisindoles and their acetate derivatives, in these and related bisindoles with similar constitution and branching of the monomeric units, is also presented.

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