Leslie Gunatilaka - Academia.edu (original) (raw)

Papers by Leslie Gunatilaka

Research paper thumbnail of Intrinsic and Extrinsic Programming of Product Chain Length and Release Mode in Fungal Collaborating Iterative Polyketide Synthases

Journal of the American Chemical Society, Aug 24, 2020

Research paper thumbnail of Abstract 3513: Promoting TRAIL apoptosis signaling using 17-beta-hydroxywithanolides

We have previously reported that withanolide E (WE), a steroidal lactone from Physalis peruviana,... more We have previously reported that withanolide E (WE), a steroidal lactone from Physalis peruviana, was highly active in sensitizing various human carcinoma cell lines to TRAIL-mediated apoptosis. Treatment of cancer cells with WE induced a reduction in the levels of the antiapoptotic proteins cFLIPL and cFLIPS, resulting in an increased activation of caspase-8 on subsequent TRAIL binding to its death receptors DR4 or DR5. The reduction in cFLIPL and cFLIPS was due to their destabilization and increased degradation by the proteasome. Interestingly, WE (a 17-beta-hydoxywithanolide, 17-BHW) was a far superior TRAIL sensitizer than more widely studied withaferin A (WFA) and its analogues, which lack the 17-beta-hydroxy group and bear an opposite side chain orientation, exhibit more promiscuous reactivity and are much more directly toxic to cells. Therefore, over 30 natural and semi-synthetic 17-BHWs were evaluated for their ability to promote death ligand-mediated cancer cell death. The 17-BHWs used in this work were obtained by the application of an efficient method of plant biomass production involving our innovative and patented soil-less aeroponic cultivation of P. crassifolia and P. peruviana and by chemical modification of natural withanolides produced by these plants. Our studies identified several 17-BHWs that were 4-8 fold more potent than WE in sensitizing the renal carcinoma cells ACHN to TRAIL-mediated apoptosis. These more active 17-BHWs were also more efficient at reducing cellular levels of cFLIPL and cFLIPS and enhancing caspase-8 activation. Preliminary structure activity relationship (SAR) studies suggested that the enone moiety in ring A was essential for activity. In addition acetoxylation at C-18, an alpha orientation of the lactone group and the double bond at C-24(25) of the lactone ring played important roles in determining the activity of 17-BHWs as TRAIL sensitizers. This suggests that the 17-BHW scaffold is amenable to optimization by a medicinal chemistry approach, which could lead to the identification of highly active natural product-based sensitizers of cancer cells to TRAIL-mediated apoptosis. The cellular molecular target(s) of active 17-BHWs are currently under further investigation. Funded by FNLCR Contract HHSN261200800001E Citation Format: Alan D. Brooks, Ya-ming Xu, E. M. Kithsiri Wijeratne, Poonam Tewary, Curtis J. Henrich, Cheryl L. Thomas, A. A. Leslie Gunatilaka, Thomas J. Sayers. Promoting TRAIL apoptosis signaling using 17-beta-hydroxywithanolides. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3513.

Research paper thumbnail of Plant Steroids: Occurrence, Biological Significance, and Their Analysis

Encyclopedia of Analytical Chemistry, Sep 18, 2020

ABSTRACT

Research paper thumbnail of Structure–Activity Relationships of Withanolides as Antiproliferative Agents for Multiple Myeloma: Comparison of Activity in 2D Models and a 3D Coculture Model

Journal of Natural Products, Aug 17, 2021

Multiple myeloma (MM) is a hematological cancer in which relapse and resistance are highly freque... more Multiple myeloma (MM) is a hematological cancer in which relapse and resistance are highly frequent. Therefore, alternatives to conventional treatments are necessary. Withaferin A, a withanolide isolated from Withania somnifera, has previously shown promising activity against various MM models. In the present study, structure-activity relationships (SARs) were evaluated using 56 withanolides. The antiproliferative activity was assessed in three MM cell lines and in a 3D MM coculture model to understand the in vitro activity of compounds in models of various complexity. While the results obtained in 2D allowed a quick and simple evaluation of cytotoxicity used for a first selection, the use of the 3D MM coculture model allowed filtering compounds that perform better in a more complex setup. This study shows the importance of the last model as a bridge between 2D and in vivo studies to select the most active compounds and ultimately lead to a reduction of animal use for more sustained in vivo studies. NF-κB inhibition was determined to evaluate if this could be one of the targeted pathways. The most active compounds, withanolide D (2) and 38, should be further evaluated in vivo.

Research paper thumbnail of Dulcitol and (-)4'-O-Methylepigallocateehin From Kokoona zeylanica

Journal of Natural Products, Mar 1, 1982

Page 1. DULCITOL AND ( -)-4'-O-METHYLEPIGALLOCATECHIN FROM KOK00,VA ZE YLANICAI G. M. KAMAL ... more Page 1. DULCITOL AND ( -)-4'-O-METHYLEPIGALLOCATECHIN FROM KOK00,VA ZE YLANICAI G. M. KAMAL B. GUSAHERATH, AA LESLIE GLTNATILAKA~ Dep(irtment of Chemistry, L'niversity of Peradeniyci, Peradeniya, Sri Lanka and and hI. UVAIS s. SCLTASBA\\..4J ...

Research paper thumbnail of Structure of a bipyridine alkaloid from Broussonetia zeylanica

Phytochemistry, 1983

Abstract From the benzene extract of the timber of Broussonetia zeylanica , 8-hydroxyquinoline-4-... more Abstract From the benzene extract of the timber of Broussonetia zeylanica , 8-hydroxyquinoline-4-aldehyde, a new alkaloid and two unidentified minor alkaloids have been isolated. The spectroscopic evidence suggested the new alkaloid to be 3,4′-dihydroxy-2,3′-bipyridine.

Research paper thumbnail of Thielavialides A–E, <i>Nor</i>-Spiro-azaphilones, and a Bis-spiro-azaphilone from <i>Thielavia</i> sp. PA0001, An Endophytic Fungus Isolated from Aeroponically Grown <i>Physalis alkekengi</i>

Journal of Natural Products, Jun 2, 2014

Research paper thumbnail of Structure-activity relationship (SAR) of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells

Investigational New Drugs, Jul 26, 2013

Research paper thumbnail of Bioactive Furanonaphthoquinones from Crescentia cujete

Journal of Natural Products, Sep 1, 1993

Bioassay-directed fractionation of the MeCOEt extract of Crescentia cujete (Bignonaceae) resulted... more Bioassay-directed fractionation of the MeCOEt extract of Crescentia cujete (Bignonaceae) resulted in the isolation of (2S,3S)-3-hydroxy-5,6-dimethoxydehydroiso-alpha-lapachone [1], (2R)-5,6-dimethoxydehydroiso-alpha-lapachone [2], (2R)-5-methoxydehydroiso-alpha-lapachone [3], 2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione [4], 5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione [5], 2-isopropenylnaphtho[2,3-b]furan-4,9-dione [6], and 5-hydroxydehydroiso-alpha-lapachone [7]. Compounds 1-3 are new, and all compounds are bioactive, showing selective activity towards DNA-repair-deficient yeast mutants. The isolation, structure elucidation, and biological activities of these compounds are reported.

Research paper thumbnail of ChemInform Abstract: SYNTHETIC USES OF STEROIDAL RING B DIENE PROTECTION- 22,23-DIHYDROERGOSTEROL

Chemischer Informationsdienst, Jul 13, 1976

Research paper thumbnail of An Analog of Withaferin A Activates the MAPK and Glutathione “Stress” Pathways and Inhibits Pancreatic Cancer Cell Proliferation

Cancer Investigation, Nov 15, 2011

Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin ... more Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin A (3)] were evaluated for antitumor activity in pancreatic cancer cells. IC(50) for 1, 2, and 3 were 0.87, 0.45, and 0.29 ?M (BxPC-3); 1.28, 1.53, and 0.52 ?M (MIAPaCa-2); and 0.59, 2.25, and 0.56 ?M (PANC-1), respectively. We chose WA analog 3 for functional studies with confirmatory RT-PCR and Western blotting. ANOVA identified 33 (MIAPaCa-2), 54 (PANC-1), and 48 (BxPC-3) gene expression changes. Fisher exact test demonstrated MAPK and glutathione pathways to be overexpressed with WA analog 3. WA analog 3 elicits a dose- and time-dependent apoptosis, activates MAPK and glutathione ?stress? pathways, and inhibits proliferation.

Research paper thumbnail of Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells

Frontiers in Pharmacology, Sep 8, 2017

Research paper thumbnail of Two Bioactive Pterocarpans from Erythrina burana

Journal of Natural Products, Oct 1, 1993

Research paper thumbnail of Bioactive and Other Sesquiterpenoids from Porella cordeana

Journal of Natural Products, Jun 1, 1993

Research paper thumbnail of Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

Nature Chemical Biology, Aug 29, 2016

Research paper thumbnail of Rational Reprogramming of <i>O</i>-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds

Journal of the American Chemical Society, Feb 15, 2019

Research paper thumbnail of Supplementary Data from Small-Molecule Natural Product Physachenolide C Potentiates Immunotherapy Efficacy by Targeting BET Proteins

Supplementary Materials &amp; Methods, Supplementary Figures 1-10 with Figure Legends

Research paper thumbnail of Natural Products of the Rhizosphere and Its Microorganisms

Research paper thumbnail of Cytotoxic Physalins from Aeroponically Grown <i>Physalis acutifolia</i>

Journal of Natural Products, Feb 14, 2021

Aeroponically grown Physalis acutifolia afforded five new and six known withanolides including 10... more Aeroponically grown Physalis acutifolia afforded five new and six known withanolides including 10 physalins. The structures of the new withanolides, acutifolactone (1), 5β,6β-epoxyphysalin C (2), 5α-chloro-6β-hydroxyphysalin C (3), and an inseparable mixture of 5β,6β-epoxy-2,3-dihydrophysalin F-3β-O-sulfate (4) and 5β,6β-epoxy-2,3-dihydrophysalin C-3β-O-sulfate (5), were elucidated by analysis of their spectroscopic data and chemical interconversions. The known withanolides were identified as physalins B (6), D (7), F (8), H (9), I (10), and U (11) by comparison of their spectroscopic data with those reported. Evaluation of 1-11 and the derivatives, 13 and 13a, obtained from 4 and 5 against a panel of four human cancer cell lines [NCI-H460 (non-small-cell lung), SF-268 (CNS glioma), PC-3 (prostate adenocarcinoma), and MCF-7 (breast adenocarcinoma)] and normal human lung fibroblast (WI-38) cells revealed that physalins 2, 3, 8, and 9 exhibited selective cytotoxic activity to at least one of the cancer cell lines tested compared to the normal cells and that 7, 10, and 11 were inactive up to a concentration of 10.0 μM. These data provided some preliminary structure-activity relationships and suggested that the mechanism of cytotoxic activity of physalins may differ from other classes of withanolides.

Research paper thumbnail of Synthesis and preliminary biological evaluation of β-carotene and retinoic acid oxidation products

Bioorganic & Medicinal Chemistry, Dec 1, 2006

ABSTRACT

Research paper thumbnail of Intrinsic and Extrinsic Programming of Product Chain Length and Release Mode in Fungal Collaborating Iterative Polyketide Synthases

Journal of the American Chemical Society, Aug 24, 2020

Research paper thumbnail of Abstract 3513: Promoting TRAIL apoptosis signaling using 17-beta-hydroxywithanolides

We have previously reported that withanolide E (WE), a steroidal lactone from Physalis peruviana,... more We have previously reported that withanolide E (WE), a steroidal lactone from Physalis peruviana, was highly active in sensitizing various human carcinoma cell lines to TRAIL-mediated apoptosis. Treatment of cancer cells with WE induced a reduction in the levels of the antiapoptotic proteins cFLIPL and cFLIPS, resulting in an increased activation of caspase-8 on subsequent TRAIL binding to its death receptors DR4 or DR5. The reduction in cFLIPL and cFLIPS was due to their destabilization and increased degradation by the proteasome. Interestingly, WE (a 17-beta-hydoxywithanolide, 17-BHW) was a far superior TRAIL sensitizer than more widely studied withaferin A (WFA) and its analogues, which lack the 17-beta-hydroxy group and bear an opposite side chain orientation, exhibit more promiscuous reactivity and are much more directly toxic to cells. Therefore, over 30 natural and semi-synthetic 17-BHWs were evaluated for their ability to promote death ligand-mediated cancer cell death. The 17-BHWs used in this work were obtained by the application of an efficient method of plant biomass production involving our innovative and patented soil-less aeroponic cultivation of P. crassifolia and P. peruviana and by chemical modification of natural withanolides produced by these plants. Our studies identified several 17-BHWs that were 4-8 fold more potent than WE in sensitizing the renal carcinoma cells ACHN to TRAIL-mediated apoptosis. These more active 17-BHWs were also more efficient at reducing cellular levels of cFLIPL and cFLIPS and enhancing caspase-8 activation. Preliminary structure activity relationship (SAR) studies suggested that the enone moiety in ring A was essential for activity. In addition acetoxylation at C-18, an alpha orientation of the lactone group and the double bond at C-24(25) of the lactone ring played important roles in determining the activity of 17-BHWs as TRAIL sensitizers. This suggests that the 17-BHW scaffold is amenable to optimization by a medicinal chemistry approach, which could lead to the identification of highly active natural product-based sensitizers of cancer cells to TRAIL-mediated apoptosis. The cellular molecular target(s) of active 17-BHWs are currently under further investigation. Funded by FNLCR Contract HHSN261200800001E Citation Format: Alan D. Brooks, Ya-ming Xu, E. M. Kithsiri Wijeratne, Poonam Tewary, Curtis J. Henrich, Cheryl L. Thomas, A. A. Leslie Gunatilaka, Thomas J. Sayers. Promoting TRAIL apoptosis signaling using 17-beta-hydroxywithanolides. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3513.

Research paper thumbnail of Plant Steroids: Occurrence, Biological Significance, and Their Analysis

Encyclopedia of Analytical Chemistry, Sep 18, 2020

ABSTRACT

Research paper thumbnail of Structure–Activity Relationships of Withanolides as Antiproliferative Agents for Multiple Myeloma: Comparison of Activity in 2D Models and a 3D Coculture Model

Journal of Natural Products, Aug 17, 2021

Multiple myeloma (MM) is a hematological cancer in which relapse and resistance are highly freque... more Multiple myeloma (MM) is a hematological cancer in which relapse and resistance are highly frequent. Therefore, alternatives to conventional treatments are necessary. Withaferin A, a withanolide isolated from Withania somnifera, has previously shown promising activity against various MM models. In the present study, structure-activity relationships (SARs) were evaluated using 56 withanolides. The antiproliferative activity was assessed in three MM cell lines and in a 3D MM coculture model to understand the in vitro activity of compounds in models of various complexity. While the results obtained in 2D allowed a quick and simple evaluation of cytotoxicity used for a first selection, the use of the 3D MM coculture model allowed filtering compounds that perform better in a more complex setup. This study shows the importance of the last model as a bridge between 2D and in vivo studies to select the most active compounds and ultimately lead to a reduction of animal use for more sustained in vivo studies. NF-κB inhibition was determined to evaluate if this could be one of the targeted pathways. The most active compounds, withanolide D (2) and 38, should be further evaluated in vivo.

Research paper thumbnail of Dulcitol and (-)4'-O-Methylepigallocateehin From Kokoona zeylanica

Journal of Natural Products, Mar 1, 1982

Page 1. DULCITOL AND ( -)-4'-O-METHYLEPIGALLOCATECHIN FROM KOK00,VA ZE YLANICAI G. M. KAMAL ... more Page 1. DULCITOL AND ( -)-4'-O-METHYLEPIGALLOCATECHIN FROM KOK00,VA ZE YLANICAI G. M. KAMAL B. GUSAHERATH, AA LESLIE GLTNATILAKA~ Dep(irtment of Chemistry, L'niversity of Peradeniyci, Peradeniya, Sri Lanka and and hI. UVAIS s. SCLTASBA\\..4J ...

Research paper thumbnail of Structure of a bipyridine alkaloid from Broussonetia zeylanica

Phytochemistry, 1983

Abstract From the benzene extract of the timber of Broussonetia zeylanica , 8-hydroxyquinoline-4-... more Abstract From the benzene extract of the timber of Broussonetia zeylanica , 8-hydroxyquinoline-4-aldehyde, a new alkaloid and two unidentified minor alkaloids have been isolated. The spectroscopic evidence suggested the new alkaloid to be 3,4′-dihydroxy-2,3′-bipyridine.

Research paper thumbnail of Thielavialides A–E, <i>Nor</i>-Spiro-azaphilones, and a Bis-spiro-azaphilone from <i>Thielavia</i> sp. PA0001, An Endophytic Fungus Isolated from Aeroponically Grown <i>Physalis alkekengi</i>

Journal of Natural Products, Jun 2, 2014

Research paper thumbnail of Structure-activity relationship (SAR) of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells

Investigational New Drugs, Jul 26, 2013

Research paper thumbnail of Bioactive Furanonaphthoquinones from Crescentia cujete

Journal of Natural Products, Sep 1, 1993

Bioassay-directed fractionation of the MeCOEt extract of Crescentia cujete (Bignonaceae) resulted... more Bioassay-directed fractionation of the MeCOEt extract of Crescentia cujete (Bignonaceae) resulted in the isolation of (2S,3S)-3-hydroxy-5,6-dimethoxydehydroiso-alpha-lapachone [1], (2R)-5,6-dimethoxydehydroiso-alpha-lapachone [2], (2R)-5-methoxydehydroiso-alpha-lapachone [3], 2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione [4], 5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione [5], 2-isopropenylnaphtho[2,3-b]furan-4,9-dione [6], and 5-hydroxydehydroiso-alpha-lapachone [7]. Compounds 1-3 are new, and all compounds are bioactive, showing selective activity towards DNA-repair-deficient yeast mutants. The isolation, structure elucidation, and biological activities of these compounds are reported.

Research paper thumbnail of ChemInform Abstract: SYNTHETIC USES OF STEROIDAL RING B DIENE PROTECTION- 22,23-DIHYDROERGOSTEROL

Chemischer Informationsdienst, Jul 13, 1976

Research paper thumbnail of An Analog of Withaferin A Activates the MAPK and Glutathione “Stress” Pathways and Inhibits Pancreatic Cancer Cell Proliferation

Cancer Investigation, Nov 15, 2011

Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin ... more Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin A (3)] were evaluated for antitumor activity in pancreatic cancer cells. IC(50) for 1, 2, and 3 were 0.87, 0.45, and 0.29 ?M (BxPC-3); 1.28, 1.53, and 0.52 ?M (MIAPaCa-2); and 0.59, 2.25, and 0.56 ?M (PANC-1), respectively. We chose WA analog 3 for functional studies with confirmatory RT-PCR and Western blotting. ANOVA identified 33 (MIAPaCa-2), 54 (PANC-1), and 48 (BxPC-3) gene expression changes. Fisher exact test demonstrated MAPK and glutathione pathways to be overexpressed with WA analog 3. WA analog 3 elicits a dose- and time-dependent apoptosis, activates MAPK and glutathione ?stress? pathways, and inhibits proliferation.

Research paper thumbnail of Withanolide D Exhibits Similar Cytostatic Effect in Drug-Resistant and Drug-Sensitive Multiple Myeloma Cells

Frontiers in Pharmacology, Sep 8, 2017

Research paper thumbnail of Two Bioactive Pterocarpans from Erythrina burana

Journal of Natural Products, Oct 1, 1993

Research paper thumbnail of Bioactive and Other Sesquiterpenoids from Porella cordeana

Journal of Natural Products, Jun 1, 1993

Research paper thumbnail of Dual action antifungal small molecule modulates multidrug efflux and TOR signaling

Nature Chemical Biology, Aug 29, 2016

Research paper thumbnail of Rational Reprogramming of <i>O</i>-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds

Journal of the American Chemical Society, Feb 15, 2019

Research paper thumbnail of Supplementary Data from Small-Molecule Natural Product Physachenolide C Potentiates Immunotherapy Efficacy by Targeting BET Proteins

Supplementary Materials &amp; Methods, Supplementary Figures 1-10 with Figure Legends

Research paper thumbnail of Natural Products of the Rhizosphere and Its Microorganisms

Research paper thumbnail of Cytotoxic Physalins from Aeroponically Grown <i>Physalis acutifolia</i>

Journal of Natural Products, Feb 14, 2021

Aeroponically grown Physalis acutifolia afforded five new and six known withanolides including 10... more Aeroponically grown Physalis acutifolia afforded five new and six known withanolides including 10 physalins. The structures of the new withanolides, acutifolactone (1), 5β,6β-epoxyphysalin C (2), 5α-chloro-6β-hydroxyphysalin C (3), and an inseparable mixture of 5β,6β-epoxy-2,3-dihydrophysalin F-3β-O-sulfate (4) and 5β,6β-epoxy-2,3-dihydrophysalin C-3β-O-sulfate (5), were elucidated by analysis of their spectroscopic data and chemical interconversions. The known withanolides were identified as physalins B (6), D (7), F (8), H (9), I (10), and U (11) by comparison of their spectroscopic data with those reported. Evaluation of 1-11 and the derivatives, 13 and 13a, obtained from 4 and 5 against a panel of four human cancer cell lines [NCI-H460 (non-small-cell lung), SF-268 (CNS glioma), PC-3 (prostate adenocarcinoma), and MCF-7 (breast adenocarcinoma)] and normal human lung fibroblast (WI-38) cells revealed that physalins 2, 3, 8, and 9 exhibited selective cytotoxic activity to at least one of the cancer cell lines tested compared to the normal cells and that 7, 10, and 11 were inactive up to a concentration of 10.0 μM. These data provided some preliminary structure-activity relationships and suggested that the mechanism of cytotoxic activity of physalins may differ from other classes of withanolides.

Research paper thumbnail of Synthesis and preliminary biological evaluation of β-carotene and retinoic acid oxidation products

Bioorganic & Medicinal Chemistry, Dec 1, 2006

ABSTRACT