1
|
Conjugates of Tetrapyrrolic Macrocycles as Potential Anticancer Target-Oriented Photosensitizers. Top Curr Chem (Cham) 2023; 381:10. [PMID: 36826755 DOI: 10.1007/s41061-023-00421-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/28/2023] [Indexed: 02/25/2023]
Abstract
Photodynamic therapy is a minimally invasive treatment of tumors using photosensitizers, light, and reactive oxygen species, which can destroy cellular structures. With the development of photodynamic therapy, significant efforts have been made to create new efficient photosensitizers with improved delivery to cells, stability, and selectivity against cancer tissues. Naturally occurring tetrapyrrolic macrocycles, such as porphyrins and chlorins, are very attractive as photosensitizers, and their structural modification and conjugation with other biologically active molecules are promising approaches for creating new photosensitizers specifically targeting cancer cells. The present review aims to highlight recent developments in the design, preparation, and investigation of complex conjugates of tetrapyrrolic macrocycles, which can potentially be used as sensitizers for target-oriented photodynamic therapy of cancer. In this review, we discuss the structure, photodynamic effect, and anticancer activity of the following conjugates of tetrapyrrolic macrocycles: (1) conjugates obtained by modifying peripheral substituents in porphyrins and chlorins; (2) conjugates of porphyrins and chlorins with lipids, carbohydrates, steroids, and peptides; (3) conjugates of porphyrins and chlorins with anticancer drugs and some other biologically active molecules; (4) metal-containing conjugates. The question of how the conjugate structure affects its specificity, internalization, localization, and photoinduced toxicity within cancer cells is the focus of this review.
Collapse
|
2
|
Pérez-Gómez CO, Vazquez-Chavez J, Yepéz R, García-Merinos JP, Ramírez-Díaz MI, del Río RE, Santillan R, López Y. Synthesis and structural characterization of an oxaziridine derived from 6-azadiosgenin. J Mol Struct 2022. [DOI: 10.1016/j.molstruc.2022.132386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
3
|
Promising applications of steroid сonjugates for cancer research and treatment. Eur J Med Chem 2020; 210:113089. [PMID: 33321260 DOI: 10.1016/j.ejmech.2020.113089] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/26/2020] [Accepted: 12/04/2020] [Indexed: 12/30/2022]
Abstract
The conjugation of biologically active molecules is a powerful tool for drug discovery used to target a variety of multifunctional diseases including cancer. Conjugated drugs can provide combination therapies in a single multi-functional agent and, by doing so, be more specific and powerful than conventional classic treatments. Steroids are widely used for conjugation with other biological active molecules. This review refers to investigations of steroid conjugates as potential anticancer agents carried out mostly over the past decade. It consists of five parts in which the data concerning structure and anticancer activity of steroid conjugates with DNA alkylating agents, metallocomplexes, approved drugs, some biological active molecules, some natural compounds and related synthetic analogs are described.
Collapse
|
4
|
Belykh DV. C–O, C–S, C–N, and C–C Bond Formation at the Periphery of the Macrocycle during Chemical Modification of Phytochlorins: Key Methods and Synthetic Applications. RUSS J GEN CHEM+ 2020. [DOI: 10.1134/s1070363219120430] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|
5
|
Gajadeera N, Hanson RN. Review of fluorescent steroidal ligands for the estrogen receptor 1995-2018. Steroids 2019; 144:30-46. [PMID: 30738074 DOI: 10.1016/j.steroids.2019.02.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 01/10/2019] [Accepted: 02/04/2019] [Indexed: 12/17/2022]
Abstract
The development of fluorescent ligands for the estrogen receptor (ER) continues to be of interest. Over the past 20 years, most efforts have focused on appending an expanding variety of fluorophores to the B-, C- and D-rings of the steroidal scaffold. This review highlights the synthesis and evaluation of derivatives substituted primarily at the 6-, 7α- and 17α-positions, culminating with our recent work on 11β-substituted estradiols, and proposes an approach to new fluorescent imaging agents that retain high ER affinity.
Collapse
Affiliation(s)
- Nisal Gajadeera
- Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston MA02115-5000, United States
| | - Robert N Hanson
- Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston MA02115-5000, United States.
| |
Collapse
|
6
|
Zolottsev VA, Ponomarev GV, Taratynova MO, Morozevich GE, Novikov RA, Timofeev VP, Solyev PN, Zavialova MG, Zazulina OV, Tkachev YV, Misharin AY. Conjugates of 17-substituted testosterone and epitestosterone with pyropheophorbide a differing in the length of linkers. Steroids 2018; 138:82-90. [PMID: 30033342 DOI: 10.1016/j.steroids.2018.06.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 06/05/2018] [Accepted: 06/08/2018] [Indexed: 12/13/2022]
Abstract
Conjugates of 17α-substituted testosterone (1 and 2) and 17β-substituted epitestosterone (3 and 4) with pyropheophorbide a were synthesized. The scheme consisted of synthesis of 17α-hydroxy-3-oxopregn-4-en-21-oic and 17β-hydroxy-3-oxopregn-4-en-21-oic acids, and their coupling with pyropheophorbide a by means of either ethylene diamine, or 1,5-diamino pentane linkers. Mutual influence of steroidal and macrocyclic fragments in conjugates molecules was dependent on configuration of C17 and length of linker, that was established by analysis of 1H NMR spectra and molecular models of conjugates. Studies of interaction of conjugates with prostate carcinoma cells revealed that their uptake and internalization were independent on the androgen receptor activity, but dependent on the structure of conjugates, decreasing in the following row: 3 > 4 ≥ 1 > 2. Conjugates significantly decreased the LNCaP and PC-3 cells growth at 96 h incubation. Epitestosterone derivatives 3 and 4 also showed superior anti-proliferative activity versus testosterone ones. Conformationally more rigid conjugates 1 and 3, comprising short linkers, were more active than those with long linkers; conjugate 3 was the most potent.
Collapse
Affiliation(s)
| | | | | | | | - Roman A Novikov
- Engelhardt Institute of Molecular Biology RAS, Moscow, Russia
| | | | - Pavel N Solyev
- Engelhardt Institute of Molecular Biology RAS, Moscow, Russia
| | | | - Olga V Zazulina
- Orekhovich Institute of Biomedical Chemistry, Moscow, Russia
| | | | | |
Collapse
|
7
|
Osati S, Ali H, Guérin B, van Lier JE. Steroid-photosensitizer conjugates: Syntheses and applications. J PORPHYR PHTHALOCYA 2018. [DOI: 10.1142/s108842461730004x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
This review focuses on progress in the development of different approaches to the design of steroid ([Formula: see text] estrogens, androgens, cholesterol) conjugates with coordination assemblies of metalloporphyrins, phthalocyanines and related complexes. Porphyrins and phthalocyanines have received considerable attention due to their novel composition, intriguing spectroscopic, photophysical, and redox properties, and potential application in light-harvesting and optoelectronic devices. With the development of more efficient imaging and therapeutic applications, these bio-conjugates are evaluated as multimodality agents (PET, fluorescence imaging) to monitor the mechanism of action of biologically active components in living systems and as agents for molecular recognition, oxygen atom transfer and catalysis. The tetrapyrrole components, which can be coupled via covalent and various non-covalent linkages, may exhibit strong interactions through efficient photo-induced electron and/or energy transfer processes.
Collapse
Affiliation(s)
- Samira Osati
- Department of nuclear medicine and radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H5N4
| | - Hasrat Ali
- Department of nuclear medicine and radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H5N4
| | - Brigitte Guérin
- Department of nuclear medicine and radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H5N4
| | - Johan E. van Lier
- Department of nuclear medicine and radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada J1H5N4
| |
Collapse
|
8
|
Kim JE, Zabula AV, Carroll PJ, Schelter EJ. 1,2-Addition or Enolization? Variable Reactivity of a Cerium Acetylide Complex toward Carbonyl Compounds. Organometallics 2016. [DOI: 10.1021/acs.organomet.6b00290] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Jee Eon Kim
- P. Roy
and Diana T. Vagelos
Laboratories, Department of Chemistry, University of Pennsylvania, 231
South 34th Street, Philadelphia, Pennsylvania 19104, United States
| | - Alexander V. Zabula
- P. Roy
and Diana T. Vagelos
Laboratories, Department of Chemistry, University of Pennsylvania, 231
South 34th Street, Philadelphia, Pennsylvania 19104, United States
| | - Patrick J. Carroll
- P. Roy
and Diana T. Vagelos
Laboratories, Department of Chemistry, University of Pennsylvania, 231
South 34th Street, Philadelphia, Pennsylvania 19104, United States
| | - Eric J. Schelter
- P. Roy
and Diana T. Vagelos
Laboratories, Department of Chemistry, University of Pennsylvania, 231
South 34th Street, Philadelphia, Pennsylvania 19104, United States
| |
Collapse
|
9
|
Tomanová P, Rimpelová S, Jurášek M, Buděšínský M, Vejvodová L, Ruml T, Kmoníčková E, Drašar PB. Trilobolide-porphyrin conjugates: on synthesis and biological effects evaluation. Steroids 2015; 97:8-12. [PMID: 25204594 DOI: 10.1016/j.steroids.2014.08.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Revised: 08/14/2014] [Accepted: 08/25/2014] [Indexed: 12/22/2022]
Abstract
Trilobolide (Tb), a potent natural counterpart of thapsigargin, is a sesquiterpene lactone of guaianolide type isolated from horse caraway (Laser trilobum, L. Borkh). Tb exerts remarkable pharmacological properties based on irreversible inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA), thus being of increasing interest for cancer cure. Additionally, another pharmacological activity of Tb, as well as of thapsigargin, was reported in several studies, Tb as being an effective inductor of nitric oxide and cytokine production. These extraordinary biological properties move these molecules in further pre-clinical evaluation. Because of ubiquitous character of SERCA expression, development of specifically targeted bioactive molecules is inevitable. Since it is well known that porphyrins are preferentially taken up by cancer cells, we have designed and synthesized novel Tb-porphyrin conjugates. Copper-catalyzed azide-alkyne cycloaddition was used to link Tb with porphyrin at once. Two model conjugates of Tb and porphyrin were synthesized and properly characterized. Employing naturally occurring fluorescence properties of porphyrins, we investigated the intracellular localization of the conjugates employing fluorescence microscopy in living cells. Intriguingly, the prepared conjugates localized both in mitochondria and lysosomes of HeLa and LNCaP cells. Furthermore, the cytotoxicity of Tb-porphyrin conjugates was assessed in a number of human cancer cell lines and rat peritoneal cells. Likewise in cancer cell lines, viability of rat peritoneal cells was not affected by the tested conjugates. Interestingly, we observed dose-dependent nitric oxide (iNOS) production induced by the tested conjugates. The effect was related to the type of a linker used and the overall size of the molecule. Another potent immunobiological effects are under evaluation. In summary, the results presented here indicate notable immunobiological potential of the prepared Tb conjugates. Moreover, they could help to decipher the molecular mechanism of Tb for its possible biomedical applications.
Collapse
Affiliation(s)
- Pavla Tomanová
- Department of Chemistry of Natural Compounds, Institute of Chemical Technology in Prague, CZ-16628 Prague, Czech Republic
| | - Silvie Rimpelová
- Department of Biochemistry and Microbiology, Institute of Chemical Technology in Prague, CZ-166 28 Prague, Czech Republic
| | - Michal Jurášek
- Department of Chemistry of Natural Compounds, Institute of Chemical Technology in Prague, CZ-16628 Prague, Czech Republic
| | - Miloš Buděšínský
- Institute of Organic Chemistry and Biochemistry, CZ-166 10 Prague, Czech Republic
| | - Lucie Vejvodová
- Institute of Pharmacology and Toxicology and Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, CZ-301 66 Pilsen, Czech Republic
| | - Tomáš Ruml
- Department of Biochemistry and Microbiology, Institute of Chemical Technology in Prague, CZ-166 28 Prague, Czech Republic
| | - Eva Kmoníčková
- Institute of Pharmacology and Toxicology and Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, CZ-301 66 Pilsen, Czech Republic.
| | - Pavel B Drašar
- Department of Chemistry of Natural Compounds, Institute of Chemical Technology in Prague, CZ-16628 Prague, Czech Republic.
| |
Collapse
|
10
|
Lamberti MJ, Vittar NBR, Rivarola VA. Breast cancer as photodynamic therapy target: Enhanced therapeutic efficiency by overview of tumor complexity. World J Clin Oncol 2014; 5:901-907. [PMID: 25493228 PMCID: PMC4259952 DOI: 10.5306/wjco.v5.i5.901] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Revised: 04/04/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
Photodynamic therapy is a minimally invasive and clinically approved procedure for eliminating selected malignant cells with specific light activation of a photosensitizer agent. Whereas interstitial and intra-operative approaches have been investigated for the ablation of a broad range of superficial or bulky solid tumors such as breast cancer, the majority of approved photodynamic therapy protocols are for the treatment of superficial lesions of skin and luminal organs. This review article will discuss recent progress in research focused mainly on assessing the efficacies of various photosensitizers used in photodynamic therapy, as well as the combinatory strategies of various therapeutic modalities for improving treatments of parenchymal and/or stromal tissues of breast cancer solid tumors. Cytotoxic agents are used in cancer treatments for their effect on rapidly proliferating cancer cells. However, such therapeutics often lack specificity, which can lead to toxicity and undesirable side effects. Many approaches are designed to target tumors. Selective therapies can be established by focusing on distinctive intracellular (receptors, apoptotic pathways, multidrug resistance system, nitric oxide-mediated stress) and environmental (glucose, pH) differences between tumor and healthy tissue. A rational design of effective combination regimens for breast cancer treatment involves a better understanding of the mechanisms and molecular interactions of cytotoxic agents that underlie drug resistance and sensitivity.
Collapse
|
11
|
Kim JE, Weinberger DS, Carroll PJ, Schelter EJ. Synthesis, Structural Characterization, and Carbonyl Addition Reactivity of a Terminal Cerium(III) Acetylide Complex. Organometallics 2014. [DOI: 10.1021/om500899z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Jee Eon Kim
- P. Roy
and Diana T. Vagelos
Laboratories, Department of Chemistry, University of Pennsylvania, 231
South 34th Street, Philadelphia, Pennsylvania 19104, United States
| | - David S. Weinberger
- P. Roy
and Diana T. Vagelos
Laboratories, Department of Chemistry, University of Pennsylvania, 231
South 34th Street, Philadelphia, Pennsylvania 19104, United States
| | - Patrick J. Carroll
- P. Roy
and Diana T. Vagelos
Laboratories, Department of Chemistry, University of Pennsylvania, 231
South 34th Street, Philadelphia, Pennsylvania 19104, United States
| | - Eric J. Schelter
- P. Roy
and Diana T. Vagelos
Laboratories, Department of Chemistry, University of Pennsylvania, 231
South 34th Street, Philadelphia, Pennsylvania 19104, United States
| |
Collapse
|
12
|
Nieland A, Mix A, Neumann B, Stammler HG, Mitzel NW. Rare-Earth-Metal Dialkynyl Dimethyl Aluminates. Chemistry 2013; 19:8268-75. [DOI: 10.1002/chem.201300465] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Indexed: 11/11/2022]
|
13
|
Lanthanides and actinides: Annual survey of their organometallic chemistry covering the year 2011. Coord Chem Rev 2013. [DOI: 10.1016/j.ccr.2012.12.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
|