A 40-Year Journey in Search of Selective Antiviral Chemotherapy*

Abstract

My search for a selective antiviral chemotherapy started more than 40 years ago with interferon inducers, then shifted to nucleoside analogs with the discovery of BVDU (brivudin), a highly selective anti-HSV-1 and anti-VZV agent, and to dideoxynucleoside analogs such as d4T (stavudine), anti-HIV agents. The search culminated in the discovery of acyclic nucleoside phosphonates (ANPs) (in collaboration with Antonin Holý), a key class of compounds active against HIV, hepatitis B virus, and DNA viruses at large; the best known of these compounds is tenofovir. Along the way, the principle of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) was established. This work, initiated in collaboration with the late Paul A.J. Janssen, eventually led to the identification of rilpivirine as perhaps an "ideal" NNRTI.1

Bis[3‐(diethoxyphosphoryl)propyl]diallylammonium chloride: Synthesis and use of its cyclopolymer as an antiscalant

“…Polymer 5 or 7 even after extended dialysis contains ≈ 4% residual alkene presumably as a result of some chain propagation without cyclization . The integration of the C [Figure (b,c)] as well as P peaks of CPE 5 (see Experimental) revealed a 75/25 cis‐trans ratio of the configurational isomers of pyrrolidinium ring at C b , b which is similar to the earlier findings (Scheme ) …”

“…δ H (D 2 O) 1.51 (4H, dt, J = 18.3 and 7.4 Hz), 1.75 (4H, m), 3.04 (4H, m), 3.64 (4H, d, J = 7.3 Hz), 5.42 (4H, m), 5.72 (2H, m), (HOD: 4.65); δ C (D 2 O) 15.87 (2C, s, PCH 2 CH 2 ), 23.32 2C, (d, PCH 2 , J (PC) 140 Hz), 58.28 (2C, d, PCH 2 CH 2 CH 2 , J (PC) 18.6 Hz), 61.37 (2C, =CH‐CH 2 , s), 124.10 (2C, s, CH 2 =CH), 129.20 (2C, s, CH 2 =CH) (dioxane: 67.40 ppm); δ P (202 MHz, D 2 O): 26.00 (m). The DEPT 135 NMR analysis supported the C spectral assignments.…”

“…The 1 H and C NMR spectra of 4 , 5 , and 7 are displayed in Figures and , respectively. The absence of the OCH 2 CH 3 signals in the spectra of 7 indicates its removal by hydrolysis [Figures (c) and (c)].…”

Bis[3‐(diethoxyphosphoryl)propyl]diallylammonium chloride: Synthesis and use of its cyclopolymer as an antiscalant

“…Polymer 5 or 7 even after extended dialysis contains ≈ 4% residual alkene presumably as a result of some chain propagation without cyclization . The integration of the C [Figure (b,c)] as well as P peaks of CPE 5 (see Experimental) revealed a 75/25 cis‐trans ratio of the configurational isomers of pyrrolidinium ring at C b , b which is similar to the earlier findings (Scheme ) …”

“…δ H (D 2 O) 1.51 (4H, dt, J = 18.3 and 7.4 Hz), 1.75 (4H, m), 3.04 (4H, m), 3.64 (4H, d, J = 7.3 Hz), 5.42 (4H, m), 5.72 (2H, m), (HOD: 4.65); δ C (D 2 O) 15.87 (2C, s, PCH 2 CH 2 ), 23.32 2C, (d, PCH 2 , J (PC) 140 Hz), 58.28 (2C, d, PCH 2 CH 2 CH 2 , J (PC) 18.6 Hz), 61.37 (2C, =CH‐CH 2 , s), 124.10 (2C, s, CH 2 =CH), 129.20 (2C, s, CH 2 =CH) (dioxane: 67.40 ppm); δ P (202 MHz, D 2 O): 26.00 (m). The DEPT 135 NMR analysis supported the C spectral assignments.…”

“…The 1 H and C NMR spectra of 4 , 5 , and 7 are displayed in Figures and , respectively. The absence of the OCH 2 CH 3 signals in the spectra of 7 indicates its removal by hydrolysis [Figures (c) and (c)].…”

Synthesis of an Apionucleoside Family and Discovery of a Prodrug with Anti-HIV Activity

“…21 Nucleophilic attack of the ketone with lithiated benzyloxymethyltributyltin afforded 16 in acceptable yield, 22 to undergo self-condensation to the aldol dimer. 23 The NMR spectra of 16 were in accordance with reported data, 20 and C-3 stereochemistry was further confirmed by a two-dimensional (2D) 1 H− 1 H NOESY experiment. One-pot acid hydrolysis and acetylation of 16 gave the triacetylated apiose 17 in a 2:1 α/β anomeric ratio.…”

Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions

“…S4A). BVDU can act as an antiviral agent against herpes simplex virus type 1 and varicella-zoster virus (VSV) and is approved for the treatment of herpes zoster (shingles) in several European countries ( 49 , 50 ). Like the case for other pyrimidine nucleoside analogs, evidence indicates that BVDU can be metabolized to effector products upon cell entry ( 50 – 52 ).…”

Bis[3‐(diethoxyphosphoryl)propyl]diallylammonium chloride: Synthesis and use of its cyclopolymer as an antiscalant

“…Polymer 5 or 7 even after extended dialysis contains ≈ 4% residual alkene presumably as a result of some chain propagation without cyclization . The integration of the C [Figure (b,c)] as well as P peaks of CPE 5 (see Experimental) revealed a 75/25 cis‐trans ratio of the configurational isomers of pyrrolidinium ring at C b , b which is similar to the earlier findings (Scheme ) …”

“…δ H (D 2 O) 1.51 (4H, dt, J = 18.3 and 7.4 Hz), 1.75 (4H, m), 3.04 (4H, m), 3.64 (4H, d, J = 7.3 Hz), 5.42 (4H, m), 5.72 (2H, m), (HOD: 4.65); δ C (D 2 O) 15.87 (2C, s, PCH 2 CH 2 ), 23.32 2C, (d, PCH 2 , J (PC) 140 Hz), 58.28 (2C, d, PCH 2 CH 2 CH 2 , J (PC) 18.6 Hz), 61.37 (2C, =CH‐CH 2 , s), 124.10 (2C, s, CH 2 =CH), 129.20 (2C, s, CH 2 =CH) (dioxane: 67.40 ppm); δ P (202 MHz, D 2 O): 26.00 (m). The DEPT 135 NMR analysis supported the C spectral assignments.…”

“…The 1 H and C NMR spectra of 4 , 5 , and 7 are displayed in Figures and , respectively. The absence of the OCH 2 CH 3 signals in the spectra of 7 indicates its removal by hydrolysis [Figures (c) and (c)].…”

Synthesis of an Apionucleoside Family and Discovery of a Prodrug with Anti-HIV Activity

“…21 Nucleophilic attack of the ketone with lithiated benzyloxymethyltributyltin afforded 16 in acceptable yield, 22 to undergo self-condensation to the aldol dimer. 23 The NMR spectra of 16 were in accordance with reported data, 20 and C-3 stereochemistry was further confirmed by a two-dimensional (2D) 1 H− 1 H NOESY experiment. One-pot acid hydrolysis and acetylation of 16 gave the triacetylated apiose 17 in a 2:1 α/β anomeric ratio.…”

Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions

“…S4A). BVDU can act as an antiviral agent against herpes simplex virus type 1 and varicella-zoster virus (VSV) and is approved for the treatment of herpes zoster (shingles) in several European countries ( 49 , 50 ). Like the case for other pyrimidine nucleoside analogs, evidence indicates that BVDU can be metabolized to effector products upon cell entry ( 50 – 52 ).…”

Bis[3‐(diethoxyphosphoryl)propyl]diallylammonium chloride: Synthesis and use of its cyclopolymer as an antiscalant

“…Polymer 5 or 7 even after extended dialysis contains ≈ 4% residual alkene presumably as a result of some chain propagation without cyclization . The integration of the C [Figure (b,c)] as well as P peaks of CPE 5 (see Experimental) revealed a 75/25 cis‐trans ratio of the configurational isomers of pyrrolidinium ring at C b , b which is similar to the earlier findings (Scheme ) …”

“…δ H (D 2 O) 1.51 (4H, dt, J = 18.3 and 7.4 Hz), 1.75 (4H, m), 3.04 (4H, m), 3.64 (4H, d, J = 7.3 Hz), 5.42 (4H, m), 5.72 (2H, m), (HOD: 4.65); δ C (D 2 O) 15.87 (2C, s, PCH 2 CH 2 ), 23.32 2C, (d, PCH 2 , J (PC) 140 Hz), 58.28 (2C, d, PCH 2 CH 2 CH 2 , J (PC) 18.6 Hz), 61.37 (2C, =CH‐CH 2 , s), 124.10 (2C, s, CH 2 =CH), 129.20 (2C, s, CH 2 =CH) (dioxane: 67.40 ppm); δ P (202 MHz, D 2 O): 26.00 (m). The DEPT 135 NMR analysis supported the C spectral assignments.…”

“…The 1 H and C NMR spectra of 4 , 5 , and 7 are displayed in Figures and , respectively. The absence of the OCH 2 CH 3 signals in the spectra of 7 indicates its removal by hydrolysis [Figures (c) and (c)].…”

Synthesis of an Apionucleoside Family and Discovery of a Prodrug with Anti-HIV Activity

“…21 Nucleophilic attack of the ketone with lithiated benzyloxymethyltributyltin afforded 16 in acceptable yield, 22 to undergo self-condensation to the aldol dimer. 23 The NMR spectra of 16 were in accordance with reported data, 20 and C-3 stereochemistry was further confirmed by a two-dimensional (2D) 1 H− 1 H NOESY experiment. One-pot acid hydrolysis and acetylation of 16 gave the triacetylated apiose 17 in a 2:1 α/β anomeric ratio.…”

Conditional lethality profiling reveals anticancer mechanisms of action and drug-nutrient interactions

“…S4A). BVDU can act as an antiviral agent against herpes simplex virus type 1 and varicella-zoster virus (VSV) and is approved for the treatment of herpes zoster (shingles) in several European countries ( 49 , 50 ). Like the case for other pyrimidine nucleoside analogs, evidence indicates that BVDU can be metabolized to effector products upon cell entry ( 50 – 52 ).…”