Synthesis and anti-HIV evaluation of hybrid-type prodrugs conjugating HIV integrase inhibitors with d4t by self-cleavable spacers containing an amino acid residue

Figures & data

Figure 1 Chemical Structures of Representative α,γ-Diketo-Based Integrase and the Nucleoside Reverse Transcriptase Inhibitor (the 2′,3′-didehydro-2′,3′-dideoxythymidine).

Figure 2 Modifications carried out on the [L-708,906]-PABC-[d4T] heterodimer prototype.

Figure 3 Design and proposed mechanism of conversion of double-drugs to d4T and IN inhibitor: Hydrolysis of the peptide linkage between the DKA and the amino acid residue (L-alanine).

Figure 4 Design and proposed mechanism of conversion of double-drugs to d4T and IN inhibitor: Hydrolysis of the peptide linkage between the amino acid residue (L-alanine) and the PABC spacer.

Scheme 1 Synthesis of [DKA]-Alanyl-PABC-[d4T] (7a–c) and [DKA]-Alanyl-OABC-[d4T] (8a–c) conjugates.

Table I.  Antiviral and Cytotoxicity Evaluation of Precursors 2a–c, 3a–c, 4a–c and 5a–c and the conjugates [INI]-spacer-[d4T] (7a–c and 8a–c) against Selected HIV Strains.

			CEM-SS HIV LAI		MT-4 HIV-1 IIIB		PBMC HIV-2 D194
Compd		R	IC50 (μM)*	CC50 (μM)^†	IC50 (μM)	CC50 (μM)	IC50 (μM)	CC50 (μM)
2a	3,5-di-OBn	OCH3	> 10	> 10	> 10	> 10	> 10	> 10
2b	3-OBn	OCH3	> 10	> 10	> 10	> 10	> 10	> 10
2c	4-OBn	OCH3	> 10	> 10	> 10	> 10	> 10	> 10
3a	3,5-di-OBn	OH	11.4 ± 2.6	73.5 ± 16.5	> CC50	63.5 ± 26.5	36 ± 1	43.5 ± 1.5
3b	3-OBn	OH	13.1 ± 11	> 100	> 100	> 100	62 ± 33	> 100
3c	4-OBn	OH	> CC50	96 ± 2	> CC50	61.5 ± 31.5	> CC50	88
4a	3,5-di-OBn	NH-PAB-OH	> 10	> 10	> 10	> 10	> 10	> 10
4b	3-OBn	NHPAB-OH	> 10	> 10	> 10	> 10	> 10	> 10
4c	4-OBn	NHPAB-OH	> 10	> 10	> 10	> 10	> 10	> 10
5a	3,5-di-OBn	NH-OAB-OH	6.4 ± 0.6	> 10	> CC50	7.65 ± 2.25	5.15 ± 1.95	6.75 ± 1.65
5b	3-OBn	NH-OAB-OH	> 10	> 10	> 10	> 10	> 10	> 10
5c	4-OBn	NH-OAB-OH	> 10	> 10	> 10	> 10	> 10	> 10
7a	3,5-di-OBn	NH-PABC-d4T	1.48 ± 0.72	> 10	4.55 ± 3.25	> 10	3.85 ± 1.95	> 10
7b	3-OBn	NH-PABC-d4T	0.52 ± 0.19	> 10	3.0 ± 2.3	> 10	3.19 ± 2.50	> 10
7c	4-OBn	NH-PABC-d4T	1.24 ± 0.46	> 10	> 10	> 10	> 10	> 10
8a	3,5-di-OBn	NH-OABC-d4T	3.4 ± 0.2	> 10	> CC50	5.15 ± 1.85	1.15 ± 0.15	7.04 ± 0.6
8b	3-OBn	NH-OABC-d4T	1.95 ± 0.05	> 10	> 10	> 10	3.55 ± 1.45	> 10
8c	4-OBn	NH-OABC-d4T	5.05 ± 2.95	> 10	> 10	> 10	> 10	> 10
d4T			0.26 ± 0.22	> 100	0.29 ± 0.11	> 100	2.57 ± 1.80	64.7 ± 29.7
AZT			0.004 ± 0.003		0.012 ± 0.005		0.006 ± 0.004

All data represent the mean values of three separate experiments ( ± SD). *IC₅₀ is the concentration required to inhibit HIV-1 multiplication by 50%. ^†CC₅₀ is the concentration drug which causes 50% cytotoxicity to uninfected cells.