Exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology

Abstract

Over the last three decades, my engagement in "fluorine chemistry" has evolved substantially because of the multidisciplinary nature of the research programs. I began my research career as a synthetic chemist in organometallic chemistry and homogeneous catalysis directed toward organic synthesis. Then, I was brought into a very unique world of "fluorine chemistry" in the end of 1970s. I started exploring the interface of fluorine chemistry and transition metal homogeneous catalysis first, which was followed by amino acids, peptides, and peptidomimetics for medicinal chemistry. Since then, I have been exploring the interfaces of fluorine chemistry and multidisciplinary fields of research involving medicinal chemistry, chemical biology, cancer biology, and molecular imaging. This perspective intends to cover my fruitful endeavor in the exploration of fluorine chemistry at the multidisciplinary interface of chemistry and biology in a chronological order to show the evolution of my research interest and strategy.

Figure 1

Homo- and block co-polymers of 2-TFMAA esters

Figure 2

Representative biologically active compounds of medicinal interest bearing an α-hydroxy-β-amino acid residue

Figure 3

Chemical structures of paclitaxel and decetaxel

Figure 4

Paclitaxel conformations in aprotic solvent (I) and in aqueous solution (II)

Figure 5

Paclitaxel and docetaxel fluorine probes for NMR analysis

Figure 6

Newman projections of the isoserine moieties of the three conformers of F₂-paclitaxel identified

Figure 7

Three conformers of F2-paclitaxel identified

Figure 8

Determination of the F-F distance in F2-10-Ac-paclitaxel using the RFDR protocol by solid state MAS ¹⁹F NMR spectroscopy

Figure 9

Selected 2^nd-generation taxoids

Figure 10

Primary sites of hydroxylation on the 2^nd-generation taxoids by cytochrome P450 family enzyme 3A4

Figure 11

Solid-state NMR studies on microtubule-bound fluorotaxoid probes

Figure 12

Three fluorotaxoids used for molecular modeling analysis

Figure 13

Computer-generated protein-bound structures of 3′-Rf-taxoids in β-tubulin 1JFF: (a) SB-T-1284 (3′-CF₂H); (b) SB-T-1282 (3′-CF₃); (c) SB-T-12853 (3′-CF₂=CH); (d) Overlay of SB-T-12853 and SB-T-1213 (3′-isobutenyl).

Figure 14

General structures of tumor-targeted drug delivery systems

Figure 15

Omega-3 polyunsaturated fatty acid–fluorotaxoid conjugates

Figure 16

mAb-taxoid conjugate with 1^st-generation disulfide linker

Figure 17

Second-generation self-immolative disulfide linker

Figure 18

Time-dependent monitoring of disulfide cleavage and thiolactonization by ¹⁹F NMR in a model system [Adapted from Ref. ]

Figure 19

Schematic representation of the RME of a drug conjugate, drug release and drug-binding to the target protein [adapted from Ref. ]

Figure 20

Vitamin-linker-taxoid conjugates bearing an imaging arm for PET analysis

Figure 21

Novel SWNT-based tumor-targeting “Trojan Horse” drug conjugate 42 and the CFM images of L1210FR cells treated with 42 incubated (A) before and (B) after the addition of GSH-ethyl ester. Image B clearly highlights the presence of fluorescent microtubule networks in the living cells generated by the binding of taxoid-fluorescein upon cleavage of the disulfide bond in the linker by either GSH or GSH-ethyl ester. [CFM images were adapted from Ref.]

Figure 22

Novel SWNT-based tumor-targeting “Trojan Horse” drug conjugate 43, bearing a fluorine probe

Figure 23

Tumor-targeted drug delivery system based on an asymmetric bowtie PAMAM dendrimer designed for the targeted delivery of 2^nd-generation taxoid/fluorotaxoid, bearing an imaging arm

Scheme 1

Hydroformylation of TFP catalyzed by Co, Pt, Ru and Rh complexes

Scheme 2

Mechanism of highly regioselective hydroformylation of fluoro-olefins

Scheme 3

Pd-catalyzed hydroesterification and hydrocarboxylation of TFP and PFS

Scheme 4

Synthesis of trifluoroleucine and trifluoronorleucine from 2-TFMPA and 3-TFMPA via azlactones

Scheme 5

Mechanism of Pd-catalyzed ureidocarbonylation of 2-Br-TFP

Scheme 6

Hydroformylation-amidocarbonylation of TFP

Scheme 7

Hydroformylation-amidocarbonylation of PFS

Scheme 8

Tetrafluoroindole synthesis from PFS via highly regioselective hydroformylation-amidocarbonylation

Scheme 9

Synthesis of (R,S)- and (S,S)-captopril-f₃

Scheme 10

Schematic illustration of modification strategy of methionine-enkephalin with trifluoronorvaline (TFNV) and trifluoronorleucine (TFNL)

Scheme 11

Preparation of racemic 3-AcO-4-isobutenyl-β-lactam via Staundinger ketene-imine cycloadditon and its subsequent enzymatic optical resolution

Scheme 12

Transformation of 3-AcO-4-isobutenyl-β-lactam to 3-TIPSO-4-CF₂H-β-lactam

Scheme 13

Preparation of 4-AcO-4-CF₃-β-lactam via Staudinger ketene-imine cycloaddition

Scheme 14

Efficient enzymatic resolution of racemic 3-AcO-F-CF₃-β-lactam

Scheme 15

Synthesis of (+)- and (−)-3-TIPS-4-CF₃-β-lactams

Scheme 16

Ring-opening coupling of 1-acyl-4-R_f-β-lactams with α- and β-amino acid esters

Scheme 17

Feasible transformations of 1-carbalkoxy-4-R_f-β-lactams to peptides and peptidomimetics

Scheme 18

Synthesis of 3′-CF₂H- and 3′-CF₃-taxoids

Scheme 19

Synthesis of C3’-difluorovinyltaxoids