Texaphyrin

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Texaphyrin general structure Texaphyrin.svg
Texaphyrin general structure

Texaphyrin is a sub-class of heterocyclic macrocycle molecules known as porphyrins. The molecule was invented by University of Texas at Austin professor Jonathan Sessler. The name texaphyrin arose because some of the molecules have a shape that can superimpose onto the points of the star featured on the state flag of Texas. [1] Texaphyrins were nominated as the "State Molecule of Texas", but the buckyball was chosen instead. [2]

Contents

Texaphyrin core Nitrogen superimpose with 5 points of the star featured on the state flag of Texas Texasflag texaphyrin Rahulsoman.jpg
Texaphyrin core Nitrogen superimpose with 5 points of the star featured on the state flag of Texas

Sessler has described possible medicinal uses of these compounds in the Proceedings of the National Academy of Sciences and other scientific journals. Pharmacyclics, Inc., a publicly traded company begun by Sessler, licensed the technology behind texaphyrins from the university to develop commercial and medical uses for the molecules. Motexafin lutetium is a texaphyrin, marketed as Antrin by Pharmacyclics Inc. It is a photosensitiser for use in photodynamic therapy to treat skin conditions and Prostate cancer. [4] Pharmacyclics and the rights to texaphyrins was sold to AbbVie in 2015 for 21 billion dollars. [5]

Synthesis of Texaphyrins

Original synthesis of texaphyrins developed by Jonathan Sessler Texaphyrinsynth.png
Original synthesis of texaphyrins developed by Jonathan Sessler

The Texaphyrin core is synthesized from the scheme shown above featuring the symmetric tri-pyrrole which is subsequently cyclized. To aromatize the texaphyrin core Sessler et al. used Cd2+, however this process was quickly replaced to allow large scale synthesis of the texaphyrin core. [6] The synthesis starts with the addition of electron rich pyrrole (I) into (II) at the C2 and C5 positions of (I), effectively displacing the acetate moiety of (II). Next, the benzyl groups are cleaved via hydrogenolysis yielding diacid (III) which is subsequently converted to the aldehyde via a decarboxylation-formylation sequence similar to a Clezy formylation. The dialdehyde is then treated with the aromatic diamine to enact an imine condensation to form the macrocyclic core of Texaphyrin. Once the core of the porphyrin has been established a final oxidation is done using air and chloroform to afford the basic Texaphyrin as a green solid. [6] The aromatic diamine can have a variety of different substituents where R is listed, and in the case of Motexafin these are polyether chains.

Texaphyrin Complexes and Chemistry

Generic texaphyrin complex and known metal centers Texaphyrin.png
Generic texaphyrin complex and known metal centers

Texaphyrin is known to make stable complexes with the elements shown in the figure, and unlike traditional porphyrins texaphyrins possess only a -1 charge instead of the typical -2. [3] Many of the metals that can form complexes with texaphyrins are metals that commonly exist in the +3-oxidation state, and part of the lanthanide series, however 12 main group metals form stable complexes as well in both the +2 and +3 oxidation state. The most common complex is with Gd (III) which is closely related to Motexafin gadolinium, used for the treatment of cancer. [7] More recently the Pb and Bi complexes have drawn attention from the Sessler groups as metal centers that could provide a more diverse array of biological applications, but little outside exploration has been done. [8] Texaphyrins have recently seen use for the detection of heavy metals in water which can be used in both a qualitative and quantitative fashion. Sessler and coworkers have employed the use of reduced texaphyrins (compound VI in the synthesis scheme) to detect heavy metals in water as these metal ions cause the texaphyrin to oxidize and subsequently change color which can be observed by the naked eye, and quantitatively measured using UV-Vis to determine the concentration of the metal ion. [9] Currently this method works for the detection of Hg(II), In(III), Cd(II), Mn(II), Bi(III), Co(II), and Pb(II) with the ability to detect amounts as low as 228 ppb. [9]

Medical Applications of Texaphyrins

Texaphyrins have seen medical applications, primarily in the form of Motexafin gadolinium and Motexafin lutetium which are used as chemotherapeutics in the treatment of cancer. The two Motexafin compounds showed initial promise compared to other texaphyrins due to the combination of water solubility and mild lipophilicity, as many other texaphyrins were too lipophilic to begin phase 1 trial. [10] Texaphyrins have an advantage over traditional porphyrins as chemotherapeutics due to the fact they are pentapyrrolic rather than the classical tetrapyrrolic allowing for a much wider range of metal centers that vary in both atomic radius and oxidation state. Texaphyrin is also unique from other porphyrins due to the fact that it is a redox active porphyrin which is easily reduced relative to other porphyrins. [11] Since texaphyrin exists in the -1 state with the ability to become -2 under physiological conditions, it has the redox active advantage over traditional porphyrins which often exist in the -2 state. This ease of reduction allows texaphyrins to act as sort of redox shuttles with the ability to produce reactive oxygen species which can subsequently induce apoptosis, providing promise as a therapeutic when localized in cancer cells. [12] When used in conjunction with targeted chemotherapy, texaphyrin is able to increase efficacy relative to the original chemotherapeutic alone as texaphyrin can prevent recovery of the cancerous cell. Texaphyrins have also shown promise as MRI contrast agents due to the fact that they are active on both T1 and T2 scans while most MRI contrast agents are only active for one type of scan. This MRI active property of texaphyrins has also led the Sessler group to explore the possibility of conjugating on existing platinum-based chemotherapeutics in order to help monitor delivery. This would allow for the minimization of off target effects from the platinum based chemotherapeutic. Conjugation of these platinum-based drugs to texaphyrin also may increases efficacy as research from the Sessler group has shown conjugation increases the concentration of intracellular platinum. [13] Despite all of these promising results the FDA gave non-approval for the texaphyrin Motexafin gadolinium shortly after finishing phase 2 clinical trials for the treatment of non-small cell lung cancer with brain metatheses, however the exact reason for its failure was not stated. [14] Shortly after non-approval Pharmacyclics announced they plan to continue to pursue candidates based on the texaphyrins in hopes of having a similar compound granted FDA approval, but neither Pharmacyclics nor the current owners of the company AbbVie, appear to have developed anything since.

Related Research Articles

The lanthanide or lanthanoid series of chemical elements comprises at least the 14 metallic chemical elements with atomic numbers 57–70, from lanthanum through ytterbium. In the periodic table, they fill the 4f orbitals. Lutetium is also sometimes considered a lanthanide, despite being a d-block element and a transition metal.

Ferrocene is an organometallic compound with the formula Fe(C5H5)2. The molecule is a complex consisting of two cyclopentadienyl rings sandwiching a central iron atom. It is an orange solid with a camphor-like odor that sublimes above room temperature, and is soluble in most organic solvents. It is remarkable for its stability: it is unaffected by air, water, strong bases, and can be heated to 400 °C without decomposition. In oxidizing conditions it can reversibly react with strong acids to form the ferrocenium cation Fe(C5H5)+2. Ferrocene and the ferrocenium cation are sometimes abbreviated as Fc and Fc+ respectively.

<span class="mw-page-title-main">Porphyrin</span> Heterocyclic organic compound with four modified pyrrole subunits

Porphyrins are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). In vertebrates, an essential member of the porphyrin group is heme, which is a component of hemoproteins, whose functions include carrying oxygen in the bloodstream. In plants, an essential porphyrin derivative is chlorophyll, which is involved in light harvesting and electron transfer in photosynthesis.

<span class="mw-page-title-main">Photodynamic therapy</span> Form of phototherapy

Photodynamic therapy (PDT) is a form of phototherapy involving light and a photosensitizing chemical substance used in conjunction with molecular oxygen to elicit cell death (phototoxicity).

<span class="mw-page-title-main">Aminolevulinic acid</span> Endogenous non-proteinogenic amino acid

δ-Aminolevulinic acid, an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals, as well as chlorophyll in plants.

<span class="mw-page-title-main">Corrole</span> Aromatic tetrapyrrole

A corrole is an aromatic tetrapyrrole. The corrin ring is also present in cobalamin (vitamin B12). The ring consists of nineteen carbon atoms, with four nitrogen atoms in the core of the molecule. In this sense, corrole is very similar to porphyrin.

<span class="mw-page-title-main">Jonathan Sessler</span> American chemist (born 1956)

Jonathan Sessler is a professor of chemistry at The University of Texas at Austin. He is notable for his pioneering work on expanded porphyrins and their applications to biology and medicine. He is a co-founder of Pharmacyclics, Inc., a company that works with expanded porphyrins, and Anionics, Inc., which develops anion recognition chemistry. Pharmacyclics was sold to AbbVie for $21 billion in 2015.

<span class="mw-page-title-main">Pentetic acid</span> DTPA: aminopolycarboxylic acid

Pentetic acid or diethylenetriaminepentaacetic acid (DTPA) is an aminopolycarboxylic acid consisting of a diethylenetriamine backbone with five carboxymethyl groups. The molecule can be viewed as an expanded version of EDTA and is used similarly. It is a white solid with limited solubility in water.

<span class="mw-page-title-main">Protoporphyrin IX</span> Chemical compound

Protoporphyrin IX is an organic compound, classified as a porphyrin, that plays an important role in living organisms as a precursor to other critical compounds like heme (hemoglobin) and chlorophyll. It is a deeply colored solid that is not soluble in water. The name is often abbreviated as PPIX.

<span class="mw-page-title-main">Motexafin gadolinium</span> Chemical compound

Motexafin gadolinium is an inhibitor of thioredoxin reductase and ribonucleotide reductase. It has been proposed as a possible chemotherapeutic agent in the treatment of brain metastases.

A nanogel is a polymer-based, crosslinked hydrogel particle on the sub-micron scale. These complex networks of polymers present a unique opportunity in the field of drug delivery at the intersection of nanoparticles and hydrogel synthesis. Nanogels can be natural, synthetic, or a combination of the two and have a high degree of tunability in terms of their size, shape, surface functionalization, and degradation mechanisms. Given these inherent characteristics in addition to their biocompatibility and capacity to encapsulate small drugs and molecules, nanogels are a promising strategy to treat disease and dysfunction by serving as delivery vehicles capable of navigating across challenging physiological barriers within the body. 

<span class="mw-page-title-main">Motexafin lutetium</span> Chemical compound

Motexafin lutetium is a texaphyrin, marketed as Antrin by Pharmacyclics Inc.

<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

<span class="mw-page-title-main">Sonodynamic therapy</span>

Sonodynamic therapy (SDT) is a noninvasive treatment, often used for tumor irradiation, that utilizes a sonosensitizer and the deep penetration of ultrasound to treat lesions of varying depths by reducing target cell number and preventing future tumor growth. Many existing cancer treatment strategies cause systemic toxicity or cannot penetrate tissue deep enough to reach the entire tumor; however, emerging ultrasound stimulated therapies could offer an alternative to these treatments with their increased efficiency, greater penetration depth, and reduced side effects. Sonodynamic therapy could be used to treat cancers and other diseases, such as atherosclerosis, and diminish the risk associated with other treatment strategies since it induces cytotoxic effects only when externally stimulated by ultrasound and only at the cancerous region, as opposed to the systemic administration of chemotherapy drugs.

<span class="mw-page-title-main">Superoxide dismutase mimetics</span> Synthetic compounds

Superoxide dismutase (SOD) mimetics are synthetic compounds that mimic the native superoxide dismutase enzyme. SOD mimetics effectively convert the superoxide anion, a reactive oxygen species, into hydrogen peroxide, which is further converted into water by catalase. Reactive oxygen species are natural byproducts of cellular respiration and cause oxidative stress and cell damage, which has been linked to causing cancers, neurodegeneration, age-related declines in health, and inflammatory diseases. SOD mimetics are a prime interest in therapeutic treatment of oxidative stress because of their smaller size, longer half-life, and similarity in function to the native enzyme.

<span class="mw-page-title-main">Abhik Ghosh</span> Indian chemist

Abhik Ghosh is an Indian inorganic chemist and materials scientist and a professor of chemistry at UiT – The Arctic University of Norway in Tromsø, Norway.

Light harvesting materials harvest solar energy that can then be converted into chemical energy through photochemical processes. Synthetic light harvesting materials are inspired by photosynthetic biological systems such as light harvesting complexes and pigments that are present in plants and some photosynthetic bacteria. The dynamic and efficient antenna complexes that are present in photosynthetic organisms has inspired the design of synthetic light harvesting materials that mimic light harvesting machinery in biological systems. Examples of synthetic light harvesting materials are dendrimers, porphyrin arrays and assemblies, organic gels, biosynthetic and synthetic peptides, organic-inorganic hybrid materials, and semiconductor materials. Synthetic and biosynthetic light harvesting materials have applications in photovoltaics, photocatalysis, and photopolymerization.

Annette Therese Byrne is an Irish physiologist, Professor and Head of the Royal College of Surgeons in Ireland (RCSI) Precision Cancer Medicine group. Her research considers metastatic colorectal cancer and glioblastoma.

<span class="mw-page-title-main">Transition metal porphyrin complexes</span>

Transition metal porphyrin complexes are a family of coordination complexes of the conjugate base of porphyrins. Iron porphyrin complexes occur widely in Nature, which has stimulated extensive studies on related synthetic complexes. The metal-porphyrin interaction is a strong one such that metalloporphyrins are thermally robust. They are catalysts and exhibit rich optical properties, although these complexes remain mainly of academic interest.

<span class="mw-page-title-main">Phosphorus porphyrin</span> Organophosphorus compound

Phosphorus-centered porphyrins are conjugated polycyclic ring systems consisting of either four pyrroles with inward-facing nitrogens and a phosphorus atom at their core or porphyrins with one of the four pyrroles substituted for a phosphole. Unmodified porphyrins are composed of pyrroles and linked by unsaturated hydrocarbon bridges often acting as multidentate ligands centered around a transition metal like Cu II, Zn II, Co II, Fe III. Being highly conjugated molecules with many accessible energy levels, porphyrins are used in biological systems to perform light-energy conversion and modified synthetically to perform similar functions as a photoswitch or catalytic electron carriers. Phosphorus III and V ions are much smaller than the typical metal centers and bestow distinct photochemical properties unto the porphyrin. Similar compounds with other pnictogen cores or different polycyclic rings coordinated to phosphorus result in other changes to the porphyrin’s chemistry.

References

  1. ↑ Adams, A. (1998). "AAAS MEETING:10-Gallon Molecule Stomps Tumors". Science. 279 (5355): 1307b–1308. doi:10.1126/science.279.5355.1307b. PMID   9508706. S2CID   12961805.
  2. ↑ Texas Legislature resolution, 1997
  3. 1 2 Preihs, Christian; Arambula, Jonathan F.; Magda, Darren; Jeong, Heeyeong; Yoo, Dongwon; Cheon, Jinwoo; Siddik, Zahid H.; Sessler, Jonathan L. (April 4, 2013). "Recent Developments in Texaphyrin Chemistry and Drug Discovery". Inorg. Chem. 52 (21): 12184–12192. doi:10.1021/ic400226g. PMC   3963820 . PMID   23557113.
  4. ↑ Hiral, Patel; Rosemarie, Mick (August 2008). "Motexafin Lutetium-Photodynamic Therapy of Prostate cancer: Short- and Long-Term Effects on Prostate-Specific Antigen". Clinical Cancer Research. 14 (15): 4869–4876. doi: 10.1158/1078-0432.CCR-08-0317 . PMC   2680073 . PMID   18676760.
  5. ↑ "AbbVie to Acquire Pharmacyclics, including its blockbuster product Imbruvica®, Creating an Industry Leading Hematological Oncology Franchise | AbbVie News Center". news.abbvie.com. Retrieved 2023-06-09.
  6. 1 2 Sessler, Jonathan L.; Hemmi, Gregory; Mody, Tarak D.; Murai, Toshiaki; Burrell, Anthony; Young, Stuart W. (1994-02-01). "Texaphyrins: Synthesis and Applications". Accounts of Chemical Research. 27 (2): 43–50. doi:10.1021/ar00038a002. ISSN   0001-4842.
  7. ↑ Sessler, Jonathan L; Miller, Richard A (2000-04-01). "Texaphyrins: New drugs with diverse clinical applications in radiation and photodynamic therapy". Biochemical Pharmacology. 59 (7): 733–739. doi:10.1016/S0006-2952(99)00314-7. ISSN   0006-2952.
  8. ↑ Preihs, Christian; Arambula, Jonathan F.; Lynch, Vincent M.; Siddik, Zahid H.; Sessler, Jonathan L. (2010-10-19). "Bismuth– and lead–texaphyrin complexes: towards potential α-core emitters for radiotherapy". Chemical Communications. 46 (42): 7900–7902. doi:10.1039/C0CC03528A. ISSN   1364-548X. PMC   3197826 .
  9. 1 2 Root, Harrison D.; Thiabaud, Gregory; Sessler, Jonathan L. (2020-02-01). "Reduced texaphyrin: A ratiometric optical sensor for heavy metals in aqueous solution". Frontiers of Chemical Science and Engineering. 14 (1): 19–27. doi:10.1007/s11705-019-1888-y. ISSN   2095-0187. PMC   10544843 .
  10. ↑ Mody, Tarak D.; Sessler, Jonathan L. (February 2001). "Texaphyrins: a new approach to drug development". Journal of Porphyrins and Phthalocyanines. 05 (02): 134–142. doi:10.1002/jpp.326. ISSN   1088-4246.
  11. ↑ Richards, Gregory M; Mehta, Minesh P (February 2007). "Motexafin gadolinium in the treatment of brain metastases". Expert Opinion on Pharmacotherapy. 8 (3): 351–359. doi:10.1517/14656566.8.3.351. ISSN   1465-6566.
  12. ↑ William, William N.; Zinner, Ralph G.; Karp, Daniel D.; Oh, Yun W.; Glisson, Bonnie S.; Phan, See-Chun; Stewart, David J. (August 2007). "Phase I Trial of Motexafin Gadolinium in Combination with Docetaxel and Cisplatin for the Treatment of Non-small Cell Lung Cancer". Journal of Thoracic Oncology. 2 (8): 745–750. doi: 10.1097/jto.0b013e31811f4719 . ISSN   1556-0864.
  13. ↑ Lee, Min Hee; Kim, Eun-Joong; Lee, Hyunseung; Kim, Hyun Min; Chang, Min Jung; Park, Sun Young; Hong, Kwan Soo; Kim, Jong Seung; Sessler, Jonathan L. (2016-12-21). "Liposomal Texaphyrin Theranostics for Metastatic Liver Cancer". Journal of the American Chemical Society. 138 (50): 16380–16387. doi:10.1021/jacs.6b09713. ISSN   0002-7863.
  14. ↑ "Pharmacyclics Receives Non-Approvable Letter from the FDA for Xcytrin for the Treatment of Lung Cancer Brain Metastases". Drugs.com. Retrieved 2023-06-09.
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