Natural and Synthetic Lactones Possessing Antitumor Activities

Abstract

Cancer is one of the leading causes of death globally, accounting for an estimated 8 million deaths each year. As a result, there have been urgent unmet medical needs to discover novel oncology drugs. Natural and synthetic lactones have a broad spectrum of biological uses including anti-tumor, anti-helminthic, anti-microbial, and anti-inflammatory activities. Particularly, several natural and synthetic lactones have emerged as anti-cancer agents over the past decades. In this review, we address natural and synthetic lactones focusing on their anti-tumor activities and synthetic routes. Moreover, we aim to highlight our journey towards chemical modification and biological evaluation of a resorcylic acid lactone, L-783277 (4). We anticipate that utilization of the natural and synthetic lactones as novel scaffolds would benefit the process of oncology drug discovery campaigns based on natural products.

Keywords: anticancer activities; drug discovery; natural lactones; natural product synthesis; synthetic lactones.

Figure 1

Structures of representative resorcylic acid lactones.

Scheme 1

The total synthesis of radicicol (1) according to Lett and Lampilas [25].

Figure 2

Retrosynthetic analysis according to Danishefsky et al. [26].

Scheme 2

Synthesis of intermediate 11 [26].

Scheme 3

Synthesis of intermediate 12 [26].

Scheme 4

Synthesis of radicicol dimethyl ether (20) [26].

Scheme 5

Synthesis of radicicol (1) according to Danishefsky et al. [27].

Scheme 6

Synthesis of radicicol (1) according to Winssinger et al. [28].

Scheme 7

Synthesis of cycloproparadicicol (32) [29].

Figure 3

Radicicol (1) analogs as Hsp90 inhibitors [30].

Figure 4

Halohydrin and oxime derivatives of radicicol (1) [31].

Scheme 8

Synthesis of triazole derivative (35) of radicicol (1) [32].

Scheme 9

Synthesis of macrolactam analog (49–52) [33].

Scheme 10

Synthesis of LL-Z1640-2 by Tatsuta et al. [41]. Reagents and conditions: (a) TMS-acetylene, n-BuLi, BF₃·Et₂O, THF, −78 °C, rt; (b) Pd(OAc)₂, CuI, Ph₃P, Et₃N, 2 h; (c) ClC(O)OEt, pyridine, 0 °C, 1 h.

Figure 5

Retrosynthesis of hypothemycin (2) and LL-Z1640-2 (3) according to Selles and Lett [42].

Scheme 11

Concise synthesis of LL-Z1640-2 (3) by Wissinger et al. [43].

Scheme 12

Total Synthesis of LL-Z1640-2 (3) by Thomas et al. [44]. Reagents and conditions: (a) CrCl₂, NiCl₂ (cat.), DMF; (b) Dess–Martin periodinane, CH₂Cl₂, rt; (c) BCl₃, CH₂Cl₂.

Scheme 13

Total synthesis of LL-Z1640-2 (3) by Barret et al. [45].

Scheme 14

The synthesis of semi-synthetic derivatives of hypothemycin (2) [46].

Scheme 15

Divergent synthesis of hypothemycin (2) and LL-Z1640-2 (3) [47].

Scheme 16

Synthesis of ER-803064 (79) [48].

Scheme 17

Synthesis of LL-Z1650-2 (3) analogs (83 and 84) [49]. Reagents and conditions: (a). (i). LiHMDS, acyclic iodide, (ii). mCPBA, Et₃N, (iii). TBAF, (iv). 2-Cl-1-Me pyridinium iodide; (b). (i). TBAF, (ii). Mitsunobu reaction, (iii). NaOH; (c). (i). PCC/Swern reaction, (ii). HCl.

Scheme 18

Synthesis of triazole derivative (90) of LL-Z1650-2 (3) [50]. Reagents and conditions: (a). (i). CuSO₄·H₂O, t-BuOH/H₂O, sodium ascorbate; (b). NaH, THF; (c). 1 N HCl, MeOH/THF.

Scheme 19

Synthesis of exo-enone analog (94) of LL-Z1640-2 (3) [51]. Reagents and conditions: (a). (i). TBSCl, imidazole, (ii). NaH, THF; (b). (i). MOMCl, NaH, (ii). TBAF, THF, (iii). DMP, DCM; (c). NiCl₂, CrCl₂, PPh₃, H₂O, DMF; (d). (i). DMP, DCM, (ii). HCl, MeOH.

Figure 6

Structures of L-783277 (4) derivatives (99 and 100).

Scheme 20

First total synthesis of L-783277 (4) by Altmann et al. [55].

Scheme 21

Synthesis of intermediates of L783277 (4) by Winssinger et al. [47].

Scheme 22

Synthesis of L783277 (4) by Winssinger et al. [47].

Scheme 23

Synthesis of fragment 118 by Sim et al. [53].

Scheme 24

Synthesis of fragment 123 by Sim et al. [53].

Scheme 25

Synthesis of fragment 124 by Sim et al. [53].

Scheme 26

Synthesis of fragment 130 by Sim et al. [53].

Scheme 27

Synthesis of L-783277 (4) by Sim et al. [53].

Scheme 28

Synthesis of fragment 139 by Nanda et al. [64].

Scheme 29

Synthesis of fragment 140 by Nanda et al. [64].

Scheme 30

Synthesis of intermediate 143 by Nanda et al. [64].

Scheme 31

Complete synthesis of L-783277 (4) by Nanda et al. [64].

Figure 7

Structure of L-783290 (147).

Scheme 32

Synthesis of fragment 149 by Banwell et al. [65].

Scheme 33

Synthesis of Fragment 152 by Banwell et al. [65].

Scheme 34

Synthesis of L-783290 (147) by Banwell et al. [65].

Scheme 35

Synthesis of 5′-deoxy analogue (158) by Altmann et al. [66].

Scheme 36

Synthesis of key intermediate 166 by Sim et al. [52].

Scheme 37

Synthesis of intermediates 169A and 169B by Sim et al. [52].

Scheme 38

Synthesis of analogs (99, 172–173) from intermediates 169A and 169B by Sim et al. [52].

Scheme 39

Synthesis of the cyclization precursor 180 by Sim et al. [54].

Scheme 40

Synthesis of rigidified analogue of L-783277 (100) by Sim et al. [54].

Figure 8

Structures of representative sesquiterpene lactones.

Figure 9

Structure of dimethylamino parthenolide, DMAPT (190).

Scheme 41

Retrosynthesis of parthenolide (183) according to Long et al. [90].

Scheme 42

Synthesis of intermediate 196 by Long et al. [90]. Reagents and conditions: (a) methyl acrylate, DABCO, RT, 77%; (b) CCl₄, n-Bu₃P, 83%; (c) HF-pyridine, THF, 91%; (d) 4 Å MS, Ti(OiPr)₄ (0.1 equiv), (–)-DIPT (0.12 equiv), TBHP (1.5 equiv), CH₂Cl₂, −40 °C to −18 °C, 93%, ee = 92%; (e) Dess–Martin periodinane, NaHCO₃, CH₂Cl₂, 92%; (f) CrCl₂, DMF; (g) DBU, CH₂Cl₂, 41% over 2 steps.

Scheme 43

Synthesis of trans-intermediate 202 by Long et al. Reagents and conditions: (a) TBDPSCl, imidazole; (b) NBS, THF/H₂O, then K₂CO₃, MeOH; (c) H₅IO₆, NaIO₄, 63% over 3 steps; (d) acrylonitrile, DABCO, RT; (e) CCl₄, n-Bu₃P, 73% over 2 steps, 27a/b = 3:1; (f) HF-Pyridine, THF; (g) 4 Å MS, Ti(OiPr)₄ (0.1 equiv), (–)-DIPT (0.12 equiv), TBHP (1.5 equiv), CH₂Cl₂, −40 °C to −18 °C; (h) Dess–Martin periodinane, NaHCO₃, CH₂Cl₂, for 28a 3 steps, 81%, ee = 97%, for 28b 3 steps, 76%, ee = 95%; (i) NaI, acetone (b) CrCl₂, THF, rt [90].

Scheme 44

Synthesis parthenolide (183) and its analog (206). Reagents and conditions: (a) K₂CO₃, H₂O₂, DMSO/THF, 86%; (b) DBU, CH₂Cl₂, rt, 92%; (c) DBU, benzene, reflux, 91%; (d) hv (254 nm), benzene, conversion: 58%, yield: 77% based on recovered starting material [90].

Scheme 45

Synthesis of dimethylamino-parthenolide analog (190). Reagents and conditions: (a) dimethylamine, MeOH, rt; (b) Fumaric acid, diethyl ether [88].

Figure 10

Preparation of parthenolide (183) and costunolide (186) from 207 [97].

Scheme 46

Synthesis of trifluoromethylated analogs (209 and 210) from 208. Reagents and conditions: (a) MnO₂, CH₂Cl₂, r.t., 8 h, 25% over 3 steps; (b) m-CPBA, CH₂Cl₂, 25 °C, 3 h, 91%. [97].

Scheme 47

Total synthesis of alantolactone (184) according to Marshall et al. [107].

Scheme 48

Synthetic transformations of alantolatone (184). Reagents and conditions: (a) CHBr₃, 50% aq. KOH, TEBAC, 5 h; (b) NaBH₄, MeOH, 25 min; (c) Mg, dry MeOH, 3 h; (d) TEA, diazomethane, overnight; (e) CF₃CO₃H, Na₂CO₃, DCM, 0 °C; (f); (g) Pd(OAc)₂/(2-MeC₆H₄)₃, trimethylamine, DMF [117,119,120].

Figure 11

Structure of DETD-35 (232).

Figure 12

Retrosynthetic analysis of Deoxyelephantopin (185) [19].

Scheme 49

(a) Synthesis of bromolactone 235; (b) synthesis of fragment 234 [19].

Scheme 50

RCM attempts by Lagoutte et al. [19].

Scheme 51

Synthesis of nordeoxyelephantophin (249) and norelephantophin (250) by Lagoutte et al. [19].

Scheme 52

Synthesis of DET-related probes (254–256) and analogs (258, 260) [134].

Scheme 53

Synthesis of DET-derivatives by Nakagawa-Goto et al. [137].

Scheme 54

Synthesis of DETD-35 (232). Reagents and conditions: (a) RCOOH, EDCI, DMAP, CH2Cl2, rt [137].

Figure 13

Structures of Costunolide Derivatives.

Scheme 55

Synthesis of costunolide (186) from dehydrosaussurea (267). Reagents and conditions: (a) 210 °C [165].

Scheme 56

Initial synthetic route for (+)-costunolide (186) According to Grieco and Nishizawa. Reagents and conditions: a, TsNHNH₂, PhH, BF₃·Et₂O; b, LDA, THF, −78 → 0 °C, 65%; c, O₃, CH₂Cl₂-MeOH (1:1), −78 °C; d, NaBH₃, −78 → 25 °C, 91%; e, NO₂C₆H₄SeCN, PBu₃, THF [165].

Scheme 57

Revised synthetic route for (+)-costunolide according to Grieco and Nishizawa. Reagents and Conditions: a, NO₂C₆H₄SeCN, Bu₃P, THF-Py (1:1); b, LDA, (PhSe)₂, HMPA, THF, −78 °C to 20 °C; c, 30% H₂O₂ in THF; d, 210 °C [165].

Scheme 58

Synthesis of costunolide (186) according to Kitagawa et al. Reagents and conditions: (a). CrCl₃-LiAlH₄ (2:1), DMF, 42%; (b). (i). TBDMSCl, (ii). 9-BBN, (iii). H₂O₂/⁻OH, 72%; (b). (i). LDA, (ii). (PhSe)₂, (iii). H₂O₂, 49% [166].

Scheme 59

Synthesis of fragments 283 and 285 by Yang et al. [97].

Scheme 60

Synthesis of intermediate 286 [97].

Scheme 61

Synthesis of (+)-costunolide (186) from the key intermediate 291. Reagents and conditions: (a) KHMDS, THF, 0 °C, 25 h, 85%; (b) Mg, MeOH, rt, 16 h, 74%; (c) PPTS, MeOH, rt, 20 min, 78%; (d) MnO₂, CH₂Cl₂, rt, 48 h, 82% [97].

Scheme 62

Synthesis of 13-amino costunolide derivatives 264 and 265 [163].

Scheme 63

Synthesis of arylated costunolide derivatives (266a–266l) [164].

Scheme 64

Synthesis of antrocin (187) from (+)-carnosic acid (292). Reagents and conditions: (a) O₃, CH₂Cl₂/MeOH (3/1), 78 °C, 1.5 h, then NaBH₄ (6.0 equiv.), 78 °C to rt, 1 h (58%); (b) Ph₃P (1.3 equiv), I₂ (1.5 equiv), imidazole (1.5 equiv), THF, 0 °C to rt, 1 h (99%); and (c) DBU (10.0 equiv), toluene, 80 °C, overnight (50%) [175].

Scheme 65

Synthesis of intermediate (−)-299 [176].

Scheme 66

Complete Synthesis of antrocin (187) [176].

Figure 14

Structure of Brevilin A (189) derivatives BA-9 (304) and BA-10 (305).

Scheme 67

Synthesis of Brevilin A (11) derivatives 304 and 305 [187].

Figure 15

DAG-Lactones as PKC ligands [189].

Figure 16

Structure of macrocyclic DAG-bis-lactones 311 [189].

Figure 17

Structure of DAG-lactones with polar 3-alkylidene chain (312–314) [195].

Figure 18

Structure of AJH-836 (315).

Scheme 68

Synthesis of DAG-bis-macrolactones [189]. Reagents and conditions: (a) (i) LiHMDS, THF, −78 °C; (ii) RCHO (13–16); (b) (i) MsCl, NEt₃, CH₂Cl₂; (ii) DBU, 45–52% in 2 steps; (c) DMAP, DMAP/HCl, DCC, CH₂Cl₂, 60–70%; (d) BCl₃, CH₂Cl₂, 80–92%.

Scheme 69

Synthesis of hydroxyl and ether DAG-lactone analogs [195]. Reagents and conditions: (a) CAN, CH₃CN–H₂O, 0 °C; (b) (CH₃)₃CCOCl, Et₃N, DMAP, CH₂Cl₂; (c) LiHMDS, CH₃(CH₂)₁₂CHO for 350–351, RO(CH₂)nCHO for 352–362, TrO(CH₂)nCHO for 363–366, THF, −78 °C; (d) (i) MsCl, NEt₃, CH₂Cl₂, (ii) DBU; (e) BCl₃, CH₂Cl₂, −78 °C; (f) CF₃CO₂H, CH₂Cl₂, 0 °C.

Scheme 70

Synthesis of AJH-836 (315). Reagents and conditions: (a). (i) LiHMDS, THF, R₂CHO, −78 °C. (ii) MsCl, CH₂Cl₂, DBU; (b) BCl₃, CH₂Cl₂, −78 °C or CAN, CH₃CN/H₂O; (c) EDC, DMAP, CH₂Cl₂, r.t.; (d) BCl₃, CH₂Cl₂, −78 °C or CAN, CH₃CN/H₂O [198].

Figure 19

Structure of andrographolide analogs.

Scheme 71

Synthesis of key intermediate 381 [218]. Reagents and conditions: (a). (i) PhMe₂SiCH₂MgCl, CeCl₃, THF, 0 °C–23 °C; (ii) 2.5 equiv MgI₂·(OEt₂)n (0.25 M in Et₂O/PhH (1:1)), PhH, 50 °C, 15 min; (iii) K₂CO₃, MeOH, 23 °C, 65%.

Scheme 72

Synthesis of andrographolide (373). Reagents and conditions: (a) 2.0 equiv SnCl₄, CH₂Cl₂, −40 °C, ca. 1 min.; (b) 1.6 equiv (S)-(−)-β-hydroxy-γ-butyrolactone, 3.2 equiv LDA, THF/HMPA (4:1), −78 °C–30 °C, 64% (80% brsm); (c) TBSCl, imidazole, DMF, 23 °C, 76%; (d) MsCl, Et₃N, CH₂Cl₂, −78 °C–0 °C, 1 h; then iPr₂NEt, CH₂Cl₂, 23 °C, 55%; (e) TBAF, THF, 23 °C, 57%; (f) HOAc/H₂O (7:3), 23 °C, 89% [218].

Scheme 73

Synthesis of cis-Decalin 391 [221].

Scheme 74

Synthesis of andrographolide (373) [221].

Figure 20

Structures of Nagilactone C, E-G (397–400).

Scheme 75

Total synthesis of nagilactone F by Hayashi et al. [229]. Reagents and conditions: (i) t-BuOK, DMSO; (j) hν; (k) NBS, CHCl₃; (l) Zn, DMF; (m) H₂SO₄; (n) H₂O; (O) Pb(OAc)₄, hν.

Figure 21

Retrosynthetic analysis of nagilactone F (399), CJ-14,445, LL-Z1271γ, Oidiolactones A-D according to Hanessian et al. [230].

Scheme 76

Synthesis of the common tricyclic precursor 409 [230].

Scheme 77

Synthesis of nagilactone F (399) from the intermediate 409 [230].