Purine Nucleosides Modified at C8 or C2 Position with (β-Halo)vinylsulfone and β-Ketosulfone Reactive Groups and Their Incorporation into DNA: Synthesis of the Organoarsenical Antibiotic Arsinothricin and Polyaromatic Hydrocarbons

Authors

Md Abu Hasan HowladerFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Chemistry

First Advisor's Name

Stanislaw F. Wnuk

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Kevin O'Shea

Second Advisor's Committee Title

committee member

Third Advisor's Name

Yi Xiao

Third Advisor's Committee Title

committee member

Fourth Advisor's Name

David Becker

Fourth Advisor's Committee Title

committee member

Fifth Advisor's Name

Marcus Cooke

Fifth Advisor's Committee Title

committee member

Sixth Advisor's Name

Alexander M. Mebel

Sixth Advisor's Committee Title

committee member

Keywords

Purine Nucleosides, (β-Halo)vinylsulfone, β-Ketosulfone, Arsinothricin, Polyaromatic Hydrocarbons

Date of Defense

6-29-2021

Abstract

Modified nucleosides gained great attention as potential anticancer and antiviral therapeutics. In this dissertation, synthesis and reactivity of (β-iodovinyl)sulfone and β-ketosulfone groups incorporated into purine nucleosides at C8 or C2 positions and DNA incorporation of their 5' triphosphates have been developed. Moreover, synthesis of novel antibiotic arsinothricin (AST) as well as polycyclic aromatic hydrocarbons (PAHs) have been discussed. The 8-(1-iodo-2-tosylvinyl)-2'-deoxyadenosine and 8-(1-Iodo-2-tosylvinyl)adenosine were synthesized employing iodovinylsulfonation of 8-ethynyl precursors with TsNa/I₂/NaOAc. The 8-(β-iodovinyl)sulfonyl-2'-deoxyguanosine was prepared via radical mediated iodovinylsulfonation of 8-ethynyl-2'-deoxyguanosine with TsNHNH₂/KI/(BzO)₂. Conformationally different C2 substituted isomeric adenosine analogues were prepared by iodovinylsulfonation of 2-alkynyl precursors with TsI/NaOAc. The (β-iodovinyl)sulfone probes underwent conjugated addition-elimination reaction with nucleophilic ammonia to give corresponding β-aminovinylsulfones. The β-ketosulfones were prepared from β-iodovinylsulfone via the intermediary β-aminovinylsulfones. The β-ketosulfones underwent efficient reactions with alkyl halides in the presence of aqueous NaOH at ambient temperature providing a diastereotopic mixture of the α-monoalkylated products. The 8-(2-tosylacetyl)-2'-deoxyadenosine was converted to its 5'-triphosphate and incorporated into double-stranded DNA by human DNA polymerase using one nucleotide gap substrates. Our work showed that the 5'-triphosphate bearing bulky β-ketosulfone group at C8 position is a good substrate for polymerase. Interesting and unexpected conversion of 2-(2-tosylacetyl)-dATP/ATP to 2-carboxylate-dATP/ATP has been observed. The 2-carboxylate-dATP efficiently incorporates into double-stranded DNA by human DNA polymerase into substrates of one nucleotide gap.

A chemoenzymatic procedure has been developed for the synthesis of antibiotic arsinothricin (AST). It involves chemical synthesis of the precursor hydroxyarsinothricin (AST-OH) from sodium arsenite via 2-chloroethyarsonic acid which was then enzymatically methylated to AST with CmArsM, the As(III)-SAM- methyltransferase. The chemical synthesis of racemic AST and the enzymatic isolation of natural L enantiomer has also been developed. It involves reduction of the N-acetyl protected analogue of AST-OH and subsequent methylation of the resulting trivalent arsenic intermediate with methyl iodide or condensation of the 2-chloroethyl(methyl)arsinic acid with diethylacetamidomalonate followed by deprotection and decarboxylation. In addition, several novel methods to synthesize polycyclic aromatic hydrocarbons and their “enyne” derivatives, as well their application as precursors or calibration compounds for the gas phase synthesis of PAHs will also be discussed.

Identifier

FIDC010275

ORCID

https://orcid.org/0000-0001-7864-2722

Previously Published In

1. A. Hasan Howlader, Keili Diaz, Alexander M. Mebel, Ralf I. Kaiser, Stanislaw F. Wnuk, Iodoindenes: Synthesis and application to cross-coupling. Tetrahedron Lett. 2020, 61, 152427.

2. Sazzad H. Suzol, A. Hasan Howlader, Adriana E. Galván, Manohar Radhakrishnan, Stanislaw F. Wnuk, Barry P. Rosen, and Masafumi Yoshinaga, Semi-synthesis of the organoarsenical antibiotic arsinothricin, J. Nat. Prod. 2020, 83, 2809.

3. Long Zhao, Srinivas Doddipatla, Ralf I. Kaiser, Wenchao Lu, Oleg Kostko, Musahid Ahmed, Lotefa Binta Tuli, Alexander N. Morozov, A. Hasan Howlader, Stanislaw F. Wnuk, Alexander M. Mebel, Valeriy N. Azyazov, Rana K. Mohamed and Felix R. Fischer, Gas Phase Synthesis of Corannulene – A Molecular Building Block of Fullerenes – in Circumstellar Envelopes, Phys. Chem. Chem. Phys. 2021, 23, 5740-5749.

4. Long Zhao, Ralf. I. Kaiser, Wenchao Lu, Musahid Ahmed, Mikhail M. Evseev, Eugene K. Bashkirov, Artem D. Oleinikov, Valeriy N. Azyazov, Alexander M. Mebel, A. Hasan Howlader, Stanislaw F. Wnuk, Gas Phase Formation of Cyclopentanaphthalene (Benzindene) Isomers via Reactions of 5- and 6-Indenyl Radicals with Vinylacetylene, Phys. Chem. Chem. Phys. 2020, 22, 22493-22500.

5. Long Zhao, Ralf. I. Kaiser, Wenchao Lu, Musahid Ahmed, Artem D. Oleinikov, Valeriy N. Azyazov, Alexander M. Mebel, A. Hasan Howlader, Stanislaw F. Wnuk, Gas phase formation of phenalene via 10π-aromatic, resonantly stabilized free radical intermediates. Phys. Chem. Chem. Phys. 2020, 22, 15381-15388.

6. Long Zhao, Ralf I. Kaiser, Wenchao Lu, Bo Xu, Musahid Ahmed, Alexander N. Morozov, Alexander M. Mebel, A. Hasan Howlader, Stanislaw F. Wnuk, Molecular mass growth through ring expansion in polycyclic aromatic hydrocarbons via radical–radical reactions. Nat. Commun. 2019, 10, 3689.

7. Long Zhao, Matthew Prendergast, Ralf I. Kaiser, Bo Xu, Utuq Ablikim, Wenchao Lu, Musahid Ahmed, Artem D. Oleinikov, Valeriy N. Azyazov, A. Hasan Howlader, Stanislaw F. Wnuk, Alexander M. Mebel, How to add a five-membered ring to polycyclic aromatic hydrocarbons (PAHs) – molecular mass growth of the 2-naphthyl radical (C₁₀H₇) to benzindenes (C₁₃H₁₀) as a case study. Phys. Chem. Chem. Phys.2019, 21, 16737-16750.

8. Long Zhao, Matthew Prendergast, Ralf. I. Kaiser, Bo Xu, Wenchao Lu, Utuq Ablikim, Musahid Ahmed, Artem D. Oleinikov, Valeriy N. Azyazov, Alexander M. Mebel, A. Hasan Howlader, Stanislaw F. Wnuk, Reactivity of the Indenyl Radical (C₉H₇) with Acetylene (C₂H₂) and Vinylacetylene (C₄H₄). ChemPhysChem 2019, 20, 1437-1447.

9. Long Zhao, Ralf I. Kaiser, Bo Xu, Utuq Ablikim, Wenchao Lu, Musahid Ahmed, Mikhail M. Evseev, Eugene K. Bashkirov, Valeriy N. Azyazov, Marsel V. Zagidullin, Alexander N. Morozov, A. Hasan Howlader, Stanislaw F. Wnuk, Alexander M. Mebel, Dharati Joshi, Gregory Veber & Felix R. Fischer, Gas phase synthesis of [4]-helicene, Nat. Commun. 2019, 10, 1510.

10. Zhiwei Wen, Paloma R. Tuttle, A. Hasan Howlader, Anna Vasilyeva, Laura Gonzalez, Antonija Tangar, Ruipeng Lei, Eduardo E. Laverde, Yuan Liu, Jaroslava Miksovska, Stanislaw F. Wnuk, Fluorescent 5-Pyrimidine and 8-Purine Nucleosides Modified with N-unsubstituted 1,2,3-Triazol-4-yl Moiety, J. Org. Chem. 2019, 84, 3624−3631.

11. Long Zhao, Bo Xu, Utuq Ablikim, Wenchao Lu, Musahid Ahmed, Mikhail M. Evseev, Eugene K. Bashkirov, Valeriy N. Azyazov, A. Hasan Howlader, Stanislaw F. Wnuk, Alexander M. Mebel, Ralf I. Kaiser, Gas-Phase Synthesis of Triphenylene (C₁₈H₁₂), ChemPhysChem 2019, 20, 791-797.

12. Sazzad H. Suzol, A. Hasan Howlader, Zhiwei Wen,Yaou Ren, Eduardo E. Laverde, Carol Garcia, Yuan Liu,and Stanislaw F. Wnuk, Pyrimidine Nucleosides with a Reactive (β-Chlorovinyl)sulfone or (β- Keto)sulfone Group at the C5 Position, Their Reactions with Nucleophiles and Electrophiles, and Their Polymerase-Catalyzed Incorporation into DNA, ACS Omega 2018, 3, 4276−4288.

13.Long Zhao, Ralf I. Kaiser, Bo Xu, Utuq Ablikim, Musahid Ahmed, Marsel Zagidullin, Valeriy Azyazov, A. Hasan Howlader, Stanislaw Wnuk, Alexander Mebel, A VUV Photoionization Study on the Formation of the Simplest Polycyclic Aromatic Hydrocarbon: Naphthalene (C₁₀H₈), J. Phys. Chem. Lett. 2018, 9, 2620−2626.

Recommended Citation

Howlader, Md Abu Hasan, "Purine Nucleosides Modified at C8 or C2 Position with (β-Halo)vinylsulfone and β-Ketosulfone Reactive Groups and Their Incorporation into DNA: Synthesis of the Organoarsenical Antibiotic Arsinothricin and Polyaromatic Hydrocarbons" (2021). FIU Electronic Theses and Dissertations. 4758.
https://digitalcommons.fiu.edu/etd/4758