Synthesis of Novel Potent Archazolids: Pharmacology of an Emerging Class of Anticancer Drugs

Abstract

Vacuolar type ATPase (V-ATPase) has recently emerged as a promising novel anticancer target based on extensive in vitro and in vivo studies with archazolids, complex polyketide macrolides, which present the most potent V-ATPase inhibitors known to date. Herein, we report a biomimetic, one-step preparation of archazolid F, the most potent and least abundant archazolid, the design and synthesis of five novel, carefully selected archazolid analogues, and the biological evaluation of these antiproliferative agents, leading to the discovery of a very potent but profoundly simplified archazolid analogue. Furthermore, the first general biological profiling of the archazolids against a broad range of more than 100 therapeutically relevant targets is reported, leading to the discovery of novel and important targets. Finally, first pharmacokinetic data of these natural products are disclosed. All of these data are relevant in the further preclinical development of the archazolids as well as the evaluation of V-ATPases as a novel and powerful class of anticancer targets.

Design, Synthesis and Biological Evaluation of Highly Potent Simplified Archazolids

“…The synthetic methodology route was subsequently used for the total synthesis of a first series of unnatural analogues. [13] The substantially simplified analogue 4 ( Figure 2) was discovered which still exhibited excellent antiproliferative activity towards several mammalian cancer cell lines, even surpassing the activity of natural archazolid F. These results confirmed our previous hypothesis that the archazolids' binding site is located in the northern, top part of the macrolactone.…”

“…This procedure was originally described by the Trauner group [15] in their total synthesis of archazolid B and had subsequently also been used by us in the preparations of archazolid F [17] and related analogues. [13] Gratifyingly, this protocol again proceeded with good selectivity (dr 10 : 1) and yields to give, after methylation with Meerwein salt, the corresponding ethers 47 a/b and 48 a/b. The protecting group at the C1 hydroxy group was then selectively removed under TBAF/AcOH conditions for the TBDPS groups of 47 a and 47 b and K 2 CO 3 for the TES groups of 48 a and 48 b.…”

“…[7][8][9][10][11][12] Furthermore, the G protein-coupled A 3adenosine receptor, the ATP-gated ion channel receptor P2X3, and human leukocyte elastase have been discovered as further molecular targets of archazolids, which may contribute to their anticancer activities. [13] The archazolids are 24-membered macrolactones with eight stereocenters, 7 double bonds and a thiazole side chain. As they are only produced in scarce quantities by nature, there is a need for a synthetic approach to provide sufficient amounts for studies on their mode of action and their target selectivity.…”

“…H and13 C signals of the final products, see the supporting information section. Optical rotations were measured with a PerkinElmer 341 polarimeter in 10 mm cuvette and are uncorrected.…”

“…Chromatography (SiO 2 , CH/EtOAc, 9 : 1) gave 20(2.38 g, 3.82 mmol, 92 %, dr > 20 : 1). R f = 0.56 (SiO 2 , CH/EtOAc, 10 : 1); [α]20 D = + 9.1°(c = 0.32, CHCl 3 ); 1 H NMR (500 MHz, CDCl 3 ): δ [ppm] = 7.75-7.66 (m, 4H), 7.49-7.38 (m, 6H), 5.84 (dq, J = 10.1, 1.4 Hz, 1H), 5.09 (dq, J = 9.1, 1.3 Hz, 1H), 4.21 (dd, J = 9.0, 5.9 Hz, 1H), 3.72 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H), 3.26-3.15 (m, 1H), 1.98 (t, J = 7.3 Hz, 2H), 1.90 (d, J = 1.4 Hz, 3H), 1.60 (d, J = 1.3 Hz, 3H), 1.58-1.48 (m, 4H), 1.07 (s, 9H), 0.96 (dd, J = 6.9, 2.6 Hz, 3H), 0.88 (s, 9H), À 0.02 (s, 3H), À 0.04 (s, 3H);13 C NMR (125 MHz, CDCl 3 ): δ [ppm] = 146.0, 135.8, 135.6, 134.1, 129.5, 127.6, 127.3, 126.4, 73.0, 63.7, 51.1, 40.8, 39.3, 32.2, 26.9, 25.8, 24.0, 21.0, 19.2, 18.1, 16.6, 16.1, À 4.1, À 4.9; HRMS (ESI +) calcd for C 37 H 58 O 4 Si 2 Na + [M + Na] + : 645.3766; found: 645.3766. Method C with [18]crown-6 (2.13 g, 8.14 mmol), 19 (1.64 g, 4.96 mmol), KHMDS (9.2 mL, 4.6 mmol) in THF (100 mL), aldehyde 21 (2.12 g, 3.54 mmol) in THF (4 mL).…”