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Palladium Biladiene Complexes Bearing Aryl Groups Through Organometallic Cross-Couplings for Sensitization of Singlet Oxygen for Photodynamic Cancer Therapy.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Palladium Biladiene Complexes Bearing Aryl Groups Through Organometallic Cross-Couplings for Sensitization of Singlet Oxygen for Photodynamic Cancer Therapy./
作者:	Rice, Anthony Thomas.
面頁冊數:	1 online resource (314 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-05, Section: B.
Contained By:	Dissertations Abstracts International84-05B.
標題:	Chemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29328168click for full text (PQDT)
ISBN:	9798351461120

Palladium Biladiene Complexes Bearing Aryl Groups Through Organometallic Cross-Couplings for Sensitization of Singlet Oxygen for Photodynamic Cancer Therapy.
Rice, Anthony Thomas.

Palladium Biladiene Complexes Bearing Aryl Groups Through Organometallic Cross-Couplings for Sensitization of Singlet Oxygen for Photodynamic Cancer Therapy. - 1 online resource (314 pages)

Source: Dissertations Abstracts International, Volume: 84-05, Section: B.

Thesis (Ph.D.)--University of Delaware, 2022.

Includes bibliographical references

Photodynamic Therapy (PDT) is an alternative treatment option for a variety of different types of cancers using a drug and activating it with light. Much research has gone into the development and modification of PDT therapeutic agents to optimize their efficacy as photosensitizers for this treatment. The first-generation PDT photosenstizer, Photofrin, is derived from hematoporphyrin and exists as a mixture of oligomers. Many second-generation photosensitizers currently in clinical trials also fall in the tetrapyrrole and porphyinoid category, mostly due to the rich photophysics of these systems. These more recently developed photosenstizers include Tookad (bacteriophorbide), Foscan (chlorin), Purlytin (etiopurpurin), and many other porphyrinoid based compounds. The major similarity between all of these is that most of these PDT agents are cyclic, aromatic tetrapyrroles. The Rosenthal research group has developed a non-aromatic, non-cyclic tetrapyrrole that we refer to as the 10,10-dimethyl-5,15-bis(pentafluorophenyl) biladiene (DMBil1) that upon metalation with palladium (Pd[DMBil1]) showed much promise as a PDT therapeutic. The promise of the parent Pd[DMBil1] led to modification of the ligand scaffold in order to shift the absorption further into the phototherapeutic window. Bromination of Pd[DMBil1] with N-bromosuccinimide yielded selective bromination of the tetrapyrrole at the 2 and 18 carbon positions, Pd[DMBilBr2]. Sonogashira coupling with various phenylacetylene groups yielded a new family of 2,18-phenylalkynyl substituted palladium centered 10,10-dimethyl-5,15-bis(pentafluorophenyl)-biladiene (Pd[DMBil2]) compounds. Extending the conjugation of the core Pd[DMBil1] showed an approximate 75 nm red-shift out into the phototherapeutic window (600-900 nm), while maintaining emissive properties such as fluorescence, phosphorescence, and 1O2 production. Electronic functionalization of the new Pd[DMBil2] directly effects the photosensitizers absorptive and emissive characteristics, with some derivatives absorbing out to 700 nm, Pd[DMBil2-NR2]; while others displayed high 1O2 quantum yields above ΦΔ = 0.90, Pd[DMBil2-CN] and Pd[DMBil2-CF3]. To further increase the magnitude of the absorption shift, larger aromatic groups were substituted onto Pd[DMBilBr2] through similar Sonogashira couplings. Derivatives of this type containing ancillary phenyl (DMBil-PE), naphthyl (DMBil-NE) and anthracene ester (DMBil-AE) groups have been prepared and characterized. We find that extension of the tetrapyrroles conjugation successfully redshifts the absorption of the DMBil-Ar family of biladienes further into the phototherapeutic window, compared to the base phenyl homologues. Pd[DMBil-AE] can sensitize the formation of 1O2 with significant quantum yields (ΦΔ = 0.66) upon irradiation with light of λ ≥ 650 nm. To further modify the dialkynyl-biladiene scaffold, we conjugated a 1,8-diethynylanthracene with to the Pd[DMBilBr2] tetrapyrrole in order to further extend the compound's p-conjugation in a cyclic loop that spans the entire tetrapyrrole unit. This new compound (Pd[DMBil2-P61]) is structurally reminiscent of the P61 Black Widow aircraft and absorbs light into the phototherapeutic window. In addition to detailing the solid-state structure and steady-state spectroscopic properties for this new biladiene, photochemical sensitization studies demonstrated that Pd[DMBil2-P61] can sensitize the formation of 1O2 with quantum yields of ΦΔ = 0.84 upon irradiation with light λ = 600 nm. Literature has shown that extending conjugation through alkenes, via Heck couplings, can increase the magnitude of absorption shift compared to extension through alkynes. This concept was applied to our Pd[DMBil1] system and the results are presented within. A Negishi coupling was performed with vinylmagnesium bromide and Pd[DMBilBr2], to yield the divinyl system Pd[DMBil1](CHCH2)2, providing electronically deficient alkenes suitable for Heck couplings. The conjugation of the tetrapyrrole was extended by coupling of various alkenyl aryl groups with the divinyl system to yield our alkene extended heck systems, Pd[DMBil3-R]. The electronics of the conjugated aryl ring has proven to have a significant effect on absorption shift as well as singlet oxygen generation (λmax = 533 - 575 nm)(ΦΔ = 0.01 - 0.94), similar to effects seen for the previous Pd[DMBil3-R] homologues.Our group has developed a molecule with a unique characteristic to address this extended photosensitivity issue. PdDMBil3-Tol is a photosensitizer candidate that absorbs light in the phototherapeutic window and generates singlet oxygen in appreciable yield (ε650 = 6,800 M-1 cm-1, ΦΔ = 0.43). Self-sensitized 1O2 forms an endoperoxide across the alkene bridge of PdDMBil3-Tol, which then cleaves to form an aldehyde on the ligand scaffold, PdDMBil3-Tol/CHO. Cleavage of one arm to form PdDMBil3-Tol/CHO leads to an asymmetric molecule with drastically reduced absorption capabilities, and singlet oxygen generation (ΦΔ = 0.08). Our intention was to incorporate both of the electronic phenomena previously shown in a single photosensitizer system. We this through the development of our mixed alkyne, PdDMBil2-CF3/N(CH3)2, with the hopes that we would be able to incorporate the redshift in the absorption from the dimethylamine group, with the high singlet oxygen generation from the trifluoromethyl group. This mixed alkyne system unfortunately displays extremely poor singlet oxygen generation (ΦΔ = 0.01 ± 0.01). This same strategy was applied to another class of extended conjugation palladium biladiene complexes with split alkene/alkyne linkers. PdDMBil4-CF3 and PdDMBil4-OCF3 were synthesized and their photophysical characteristics were analyze. PdDMBil4-CF3 displayed singlet oxygen generation capabilities similar to that of the bis-alkyne and bis-alkene homologues (ΦΔ = 0.95 ± 0.03). Again, singlet oxygen generation was limited by the half of the ligand scaffold that was more electron rich for PdDMBil4-OCF3 (ΦΔ = 0.78 ± 0.05). What we can take away from these systems is that the next generation of palladium biladiene photosensitizers must not possess electron rich aryl functionalities that limit singlet oxygen generation, despite pushing absorbance into the phototherapeutic window.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798351461120Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Palladium biladieneIndex Terms--Genre/Form:

542853
Electronic books.

Palladium Biladiene Complexes Bearing Aryl Groups Through Organometallic Cross-Couplings for Sensitization of Singlet Oxygen for Photodynamic Cancer Therapy.
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504 $a Includes bibliographical references
520 $a Photodynamic Therapy (PDT) is an alternative treatment option for a variety of different types of cancers using a drug and activating it with light. Much research has gone into the development and modification of PDT therapeutic agents to optimize their efficacy as photosensitizers for this treatment. The first-generation PDT photosenstizer, Photofrin, is derived from hematoporphyrin and exists as a mixture of oligomers. Many second-generation photosensitizers currently in clinical trials also fall in the tetrapyrrole and porphyinoid category, mostly due to the rich photophysics of these systems. These more recently developed photosenstizers include Tookad (bacteriophorbide), Foscan (chlorin), Purlytin (etiopurpurin), and many other porphyrinoid based compounds. The major similarity between all of these is that most of these PDT agents are cyclic, aromatic tetrapyrroles. The Rosenthal research group has developed a non-aromatic, non-cyclic tetrapyrrole that we refer to as the 10,10-dimethyl-5,15-bis(pentafluorophenyl) biladiene (DMBil1) that upon metalation with palladium (Pd[DMBil1]) showed much promise as a PDT therapeutic. The promise of the parent Pd[DMBil1] led to modification of the ligand scaffold in order to shift the absorption further into the phototherapeutic window. Bromination of Pd[DMBil1] with N-bromosuccinimide yielded selective bromination of the tetrapyrrole at the 2 and 18 carbon positions, Pd[DMBilBr2]. Sonogashira coupling with various phenylacetylene groups yielded a new family of 2,18-phenylalkynyl substituted palladium centered 10,10-dimethyl-5,15-bis(pentafluorophenyl)-biladiene (Pd[DMBil2]) compounds. Extending the conjugation of the core Pd[DMBil1] showed an approximate 75 nm red-shift out into the phototherapeutic window (600-900 nm), while maintaining emissive properties such as fluorescence, phosphorescence, and 1O2 production. Electronic functionalization of the new Pd[DMBil2] directly effects the photosensitizers absorptive and emissive characteristics, with some derivatives absorbing out to 700 nm, Pd[DMBil2-NR2]; while others displayed high 1O2 quantum yields above ΦΔ = 0.90, Pd[DMBil2-CN] and Pd[DMBil2-CF3]. To further increase the magnitude of the absorption shift, larger aromatic groups were substituted onto Pd[DMBilBr2] through similar Sonogashira couplings. Derivatives of this type containing ancillary phenyl (DMBil-PE), naphthyl (DMBil-NE) and anthracene ester (DMBil-AE) groups have been prepared and characterized. We find that extension of the tetrapyrroles conjugation successfully redshifts the absorption of the DMBil-Ar family of biladienes further into the phototherapeutic window, compared to the base phenyl homologues. Pd[DMBil-AE] can sensitize the formation of 1O2 with significant quantum yields (ΦΔ = 0.66) upon irradiation with light of λ ≥ 650 nm. To further modify the dialkynyl-biladiene scaffold, we conjugated a 1,8-diethynylanthracene with to the Pd[DMBilBr2] tetrapyrrole in order to further extend the compound's p-conjugation in a cyclic loop that spans the entire tetrapyrrole unit. This new compound (Pd[DMBil2-P61]) is structurally reminiscent of the P61 Black Widow aircraft and absorbs light into the phototherapeutic window. In addition to detailing the solid-state structure and steady-state spectroscopic properties for this new biladiene, photochemical sensitization studies demonstrated that Pd[DMBil2-P61] can sensitize the formation of 1O2 with quantum yields of ΦΔ = 0.84 upon irradiation with light λ = 600 nm. Literature has shown that extending conjugation through alkenes, via Heck couplings, can increase the magnitude of absorption shift compared to extension through alkynes. This concept was applied to our Pd[DMBil1] system and the results are presented within. A Negishi coupling was performed with vinylmagnesium bromide and Pd[DMBilBr2], to yield the divinyl system Pd[DMBil1](CHCH2)2, providing electronically deficient alkenes suitable for Heck couplings. The conjugation of the tetrapyrrole was extended by coupling of various alkenyl aryl groups with the divinyl system to yield our alkene extended heck systems, Pd[DMBil3-R]. The electronics of the conjugated aryl ring has proven to have a significant effect on absorption shift as well as singlet oxygen generation (λmax = 533 - 575 nm)(ΦΔ = 0.01 - 0.94), similar to effects seen for the previous Pd[DMBil3-R] homologues.Our group has developed a molecule with a unique characteristic to address this extended photosensitivity issue. PdDMBil3-Tol is a photosensitizer candidate that absorbs light in the phototherapeutic window and generates singlet oxygen in appreciable yield (ε650 = 6,800 M-1 cm-1, ΦΔ = 0.43). Self-sensitized 1O2 forms an endoperoxide across the alkene bridge of PdDMBil3-Tol, which then cleaves to form an aldehyde on the ligand scaffold, PdDMBil3-Tol/CHO. Cleavage of one arm to form PdDMBil3-Tol/CHO leads to an asymmetric molecule with drastically reduced absorption capabilities, and singlet oxygen generation (ΦΔ = 0.08). Our intention was to incorporate both of the electronic phenomena previously shown in a single photosensitizer system. We this through the development of our mixed alkyne, PdDMBil2-CF3/N(CH3)2, with the hopes that we would be able to incorporate the redshift in the absorption from the dimethylamine group, with the high singlet oxygen generation from the trifluoromethyl group. This mixed alkyne system unfortunately displays extremely poor singlet oxygen generation (ΦΔ = 0.01 ± 0.01). This same strategy was applied to another class of extended conjugation palladium biladiene complexes with split alkene/alkyne linkers. PdDMBil4-CF3 and PdDMBil4-OCF3 were synthesized and their photophysical characteristics were analyze. PdDMBil4-CF3 displayed singlet oxygen generation capabilities similar to that of the bis-alkyne and bis-alkene homologues (ΦΔ = 0.95 ± 0.03). Again, singlet oxygen generation was limited by the half of the ligand scaffold that was more electron rich for PdDMBil4-OCF3 (ΦΔ = 0.78 ± 0.05). What we can take away from these systems is that the next generation of palladium biladiene photosensitizers must not possess electron rich aryl functionalities that limit singlet oxygen generation, despite pushing absorbance into the phototherapeutic window.
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650 4 $a Biomedical engineering. $3 535387
650 4 $a Oncology. $3 751006
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