Boronated Thymidine Analogues for Boron Neutron Capture Therapy

Abstract

Concise synthetic methods for synthesizing 3-carboranyl thymidine analogues (3CTAs) modified with cyclic and acyclic alcohols have been developed. The synthesis of these potential boron neutron capture therapy (BNCT) agents and their preliminary biological evaluation is described.

Keywords:

• Boron Neutron Capture Therapy (BNCT)
• 3-Carboranyl Thymidine Analogues (3CTAs)

This work was supported by the U.S. Department of Energy grant DE-FG02–90ER60972 and grants from the Swedish Research Council. The authors thank Dianne Adams for technical assistance. Presented at the XVI International Roundtable Conference, September 12–16, 2004.

Notes

¹ 6: ¹H NMR (CD₃OD) δ: 1.84 (d, 3H, CH₃), 2.09–2.12 (m, 2H, H-2′), 3.18 (s, 1H, H-C_carborane), 3.34–3.36 (m, 1H, CH-OH), 3.51–3.52 (m, 1H, CH-OH), 3.68–3.76 (m, 3H, H-5′ and H-4′), 3.81–3.85 (m, 2H, CH₂-N), 4.08–4.17 (m, 1H, CH-OH), 4.30–4.35 (m, 1H, H-3′), 6.22 (t, 1H, H-1′), 7.79 (d, 1H, H-6); ¹³C NMR (CD₃OD) δ: 165.86 (C-4), 152.79 (C-2), 136.55 (C-6), 110.72 (C-5), 88.91 (C-4′), 87.27 (C-1′), 73.11 (C-O), 72.92 (C-O), 72.17 (C-O), 72.04 (C-3′), 62.73 (C-5′), 44.87 (CH₂-N), 41.46 (C-2′), 13.21 (CH₃); MS (HR-ESI) C₁₆H₃₂B₁₀N₂O₈Na (M+Na)⁺ calcd: 513.2987, found 513.3016.

² 14: ¹H NMR (CD₃OD) δ: 1.44–1.47 (m, 2H, CH₂), 1.66–1.70 (m, 2H, CH ₂-C_carborane), 1.88 (d, 3H, CH₃), 2.14–2.28 (m, 1H, H-2′), 3.40–3.58 (m, 5H, CH-OH and CH₂ -OH), 3.68–3.92 (m, 5H, H-4′, H-5′, and CH₂-N), 4.36–4.38 (m, 1H, H-3′), 6.27 (t, 1H, H-1′), 7.81 (d, 1H, H-6); ¹³C NMR (CD₃OD) δ: 165.28 (C-4), 152.20 (C-2), 136.58 (C-6), 110.65 (C-5), 89.11 (C-1′), 87.10 (C-4′), 75.17 (C-O), 72.66 (C-O), 72.41 (C-3′), 72.05 (C-O), 63.74 (CH₂-O), 62.73 (C-5′), 41.56 (CH₂-N), 41.29 (C-2′), 36.29 (C-C_carborane), 28.70 (CH₂), 13.14 (CH₃); MS (HR-ESI) C₁₉H₃₈B₁₀N₂O₉Na (M+Na)⁺ calcd: 569.3489, found: 569.3480.

³ 17: ¹H NMR (CDCl₃) δ: 1.47–1.50 (m, 4H, CH₂), 1.56–1.58 (m, 2H, CH₂), 1.89 (d, 3H, CH₃), 1.93–1.98 (m, 2H, CH ₂-C_carborane), 2.29–2.44 (m, 4H, CH ₂-C_carborane and H-2′), 3.78–3.98 (m, 9H, CH-OH, H-5′, H-4′, and CH₂-N), 4.58 (m, 1H, H-3′), 4.80 (d, 1H, CH(OH)-O), 6.12 (t, 1H, H-1′), 7.28 (d, 1H, H-6); ¹³C NMR (CDCl₃) δ: 162.35 (C-4), 150.78 (C-2), 135.21 (C-6), 110.78 (C-5), 109.71 (C(OH)-O), 90.17(C-O), 88.06 (C-4′), 87.18 (C-1′), 78.97 (C-O), 71.99 (C-3′), 70.72 (C-O), 62.83 (C-5′), 55.30 (C-O), 41.55 (CH₂-N), 40.88 (C-2′), 40.44 (C-C_carborane), 37.98 (C-C_carborane), 29.55 (CH₂), 27.53 (CH₂), 26.78 (CH₂), 13.71 (CH₃); MS (HR-ESI) C₂₃H₄₄B₁₀N₂O₁₀Na (M+Na)⁺ calcd: 639.3909, found: 639.3904.