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Microtubule-Targeting Compounds: Comparison
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Please note this is a comparison between Version 5 by Søren Brøgger Christensen and Version 4 by Dean Liu.

The microtubule is the target for chemotherapeutics, such as the microtubule-destabilizing compounds and the microtubule-stabilizing compounds. Both kinds of chemotherapeutics have revolutionized cancer treatment.

  • taccalonolide
  • Zamopanolide
  • microtubule-targeting agent

1. Microtubule-Destabilizing Compounds

Four binding sites have been found for microtubule-destabilizing agents: (1) the vinca site, (2) the colchicine site, (3) the maytansine site and (4) the pironetin site [1]. The vinca alkaloids bind to the plus end of β-tubulin. Eribulin binds also to the plus end but only half overlapping with the vinca alkaloids. The colchicine-binding site is located on the β-tubulin at the intradimer interface of α- and β-tubulin. The maytansine-binding site is close to the vinca site but not overlapping [1].
In the 1960s, the target for colchicine (Figure 1, 93) was identified as tubulin, which is the building block in microtubules [2]. Binding of colchicine to the tubule destabilizes the microtubule [2]. Colchicine is the major alkaloid in Cochicum autumnale L. (Colchicaceae). Herbs containing colchicine have for centuries been used in traditional medicine for the treatment of gout. Colchicine is an efficient drug. However, the toxicity prevents it from being approved [3]. Comparison of the structures of colchicine and compound 94 and combretastatin A-4 (CA-4) (95) (Figure 1) reveals the pharmacophore affording affinity for the binding domain [4]. Several other microtubule-destabilizing compounds have been identified. Podophyllotoxin (97) has been isolated from roots or rhizomes from Podophyllum species (Berberaceae). The resins were originally used as purgatives, but the discovery of the antimitotic effects made the product interesting as a chemotherapeutic [3]. The toxicity of the natural product, however, prevents its use as a drug, but the semisynthetic etoposide (98) and the water-soluble prodrug etopophos (99) is used as a drug for the treatment of small lung cancer, testicular cancer and lymphoma [3]. It is to be noted that the clinical effect of etoposide is caused by inhibition of topoisomerase II [5][6].
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Figure 1. Compounds with an affinity for the colchicine domain in tubulin. Colchicine (93), the colchicine pharmacophore 2-methoxy-5-(2′,3′,4′-trimethoxyphenyl)tropone (94) and combretastatin CA-4 (95), TN-16 (96), podophyllotoxin (97), etoposide (98), etopophos (99) and nocodazole (100) [2].
Besides the agents with an affinity for the colchicine-binding site, a group of microtubule-destabilizing compounds with affinity for the vinca domain have been characterized (Figure 2). The vinca alkaloids (101,102) have significantly improved life expectancy for patients suffering from childhood acute lymphoblastic leukemia and other cancer diseases [7].
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Figure 2. Microtubule-destabilizing agents with affinity for the vinca domain: Vinblastin (101), vincristine (102), phomopsin A (103), dolastatin 10 (104) [2][4].
Dolastatin 10 (103) was isolated from an Indian sea hare Dolabella auricularia. The compound failed as a drug for prostate cancer and metastatic melanoma in clinical trial II [4]. Dolastatin binds to a peptide-binding site near the vinca domain [4].
Halichondrin B (Figure 3, 105) is a macrolide polyketide isolated from the marine sponges Halichondria okadai. Halichondrin B binds with affinity to the vinca-binding site [4][8]. Nature could not provide the amounts of compounds needed for sustainable drug production. Instead, a simplified analogue, eribulin (106), was synthesized [4][9]. A structure-activity relationship study revealed the pharmacophore affording the affinity for microtubules resides in the right moiety of the molecule [10]. Eribulin has been approved for the treatment of metastatic breast cancer for patients who previously received two chemotherapeutic regimens [10]. In the case of halichondrin B, a sustainable supply was obtained by simplification of the molecule to give an analogue (eribulin 106), 
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Figure 3. Halichondrin B (105) and a simplified analogue, eribulin (106), are approved for the treatment of breast cancer. Maytansine 1 (107) conjugated via a linker to an antibody-targeting HER-2 has been approved for the treatment of breast cancer [4].
Maytansine 1 (107) conjugated via a linker to an HER-2 targeted antibody has been approved for the treatment of breast cancer overexpressing the HER-2 gene [4][11].

2. Microtubule-Stabilizing Compounds

Only two binding sites have been found for microtubule stabilizers 1) the taxane site and the laulimalide/peloruside site [1]. The taxane-binding site is located on the interior of the microtubule. The other binding site is on the exterior of the microtubule [1]. The taccalonolides, zampanolides and cyclostreptin bind covalently to the binding site [1].
Many natural products have been found to stabilize microtubules (Figure 4). Peloruside A (108) together with three related polyketide macrolides were isolated from the marine sponge Mycale hentscheli collected in southern New Zealand [12]. The binding site of peloruside A involves Phe294, Tyr310, Arg306 and Tyr340 of the exterior site on β-tubulin [12]. The development of peluroside into a drug has been delayed due to a supply issue [13]. Laulimalide (109) was isolated from the marine sponge Cacospongia mycofijiensis found in the Pacific Ocean [14]. Both compounds are microtubule stabilizers binding to the same binding site [12].
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Figure 4. Microtubule-stabilizing agents peluroside A (108), laulimalide (109).
The taccalonolides (Figure 5) have been isolated from Tacca chantrieri (André), Dioscoraceae, in order to characterize the principle causing bundling of interphase microtubules [15]. Other taccalonolides have been isolated from other Tacca species. Taccalonolides A (110) and E (112) shown in Figure 4 are examples of the more than 20 known steroids all possessing the same carbon skeleton. Taccalonolides B (111) and N (113) are semisynthetic analogues. Characteristics for the taccalonolides are the C-2-C-3 epoxy group and the C-23-C-24 enol γ-lactone group. Taccalonolides A, B, E and N cause bundling of interphase microtubules and mitotic arrest followed by apoptosis [15]. The taccalonolides also provoke apoptosis in cells with mutated paclitaxel-binding sites and expression of P-glycoprotein (Pgp). Even though the taccalonolides show poor in vitro activity, they have high in vivo potency. However, studies have revealed that they, in contrast to taccalonolides AF (110) and AJ (111), do not bind to microtubules. In addition, taccalonolide AF and AJ are several orders of magnitude more potent than taccalonolides A and B [16]. This has led to the hypothesis that enol esters 110 and 111 are prodrugs of epoxides 114 and 115, respectively. Taccalonolide AF has been isolated from Tacca plantaginea (Hance) [16]. However, the compound was only present in low abundance. Consequently, semisynthesis was performed using taccalonolide A as starting material. Synthesis provided enough compound to establish microtubule-stabilization activity. Taccalonolide AJ is a semisynthetic product prepared by epoxidation of taccalonolide B [16]. In early publications, the C-22-C-23 epoxide was α-disposed; later publications suggest a β-disposed epoxide [13][17].
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Figure 5. The taccanlonolides. Taccalonolides A (110) and E (112) were isolated from tubules of Tacca chantrieri. Taccalonolides B (111) and N (113) are semisynthetic analogues. Taccalonolides AF (114) and AJ (115) [15].
Cyclostreptin (Figure 6, 116) isolated from a culture of Streptomyces sp. 9885 can displace Flutax 2 (86) from microtubules. In contrast, Flutax 2 cannot displace cyclostreptin [18]. Mass spectrometric analysis of fragments of microtubules reveals that the fragment containing amino acid residues 219 to 243 gains an m/z value of 133.2 after incubation of the microtubule with cyclostreptin. Since the fragment has a charge of 3 (z = 3), this corresponds to an increased molecular weight of 400.2, corresponding to an addition of cyclostreptin to the fragment (Figure 6). It is not stated if the addition is an amide formation or a hetero Michael addition. Both Thr220 and Asn228 are suggested to be the nucleophile reagent attacking cyclostreptin [18].
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Figure 6. Possible paths for reacting cyclostreptin (116) with microtubules. Either the lactone opens forming an amide or a hetero-Michael reaction affords a 1,4-addition to the α,β-unsaturated lactone [18]. A possible reaction product (117) has been suggested.
Zampanolide (Figure 7, 118) was isolated from the marine sponge Fasciospongia rimasa and from Cacospongia mycofijiensis, although only in small amounts. Total syntheses of the compound have been developed [19][20]. Dactylolide (119) was isolated from a Dactylospongia sp. sponge [20]. Very varying measurements of optical rotations maybe because of varying degrees of enolization have complicated the establishment of the absolute configuration [19]. The missing aminal chain reduces the cytotoxicity of dactylolide by two orders of magnitude compared with zampanolide.
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Figure 7. Zampanolide (118) and dactylolide (119) and suggested products (120 and 121) formed by reacting microtubule with zampanolide [19][20].
Both zampanolide and dactylolide bind to the binding site of paclitaxel on the microtubule. An interesting feature of zampanolide is the toxicity towards multi-drug-resistant cancer cell lines expressing P-gp pump [19]. The failure of P-gp to remove zampanolide might be caused by formation of a covalent bond to the microtubules. A hetero-Michael reaction between the heterocyclic nitrogen atom of His230 to give 120 or the amide of Asn229 to give 121 and C-9 has been suggested as the reaction forming the covalent bond zampanolide (Figure 7) [19][20]. Dactyloide may react in a similar way. Other possibilities, however, are mentioned. None of the suggested nitrogen atoms, however, are likely to undergo a hetero-Michael reaction.

References

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  7. Christensen, S.B. Natural Products that Changed Society. Biomedicines 2021, 9, 472.
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  14. He, L.; Orr, G.A.; Horwitz, S.B. Novel molecules that interact with microtubules and have functional activity similar to Taxol. Drug Discov. Today 2001, 6, 1153–1164.
  15. Li, J.; Risinger, A.L.; Mooberry, S.L. Taccalonolide microtubule stabilizers. Bioorg. Med. Chem. 2014, 22, 5091–5096.
  16. Li, J.; Risinger, A.L.; Peng, J.; Chen, Z.; Hu, L.; Mooberry, S.L. Potent Taccalonolides, AF and AJ, Inform Significant Structure-Activity Relationships and Tubulin as the Binding Site of These Microtubule Stabilizers. J. Am. Chem. Soc. 2011, 133, 19064–19067.
  17. Risinger, A.L.; Hastings, S.D.; Du, L. Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities. J. Nat. Prod. 2021, 84, 1799–1805.
  18. Buey, R.M.; Calvo, E.; Barasoain, I.; Pineda, O.; Edler, M.C.; Matesanz, R.; Cerezo, G.; Vanderwal, C.D.; Day, B.W.; Sorensen, E.J.; et al. Cyclostreptin binds covalently to microtubule pores and lumenal taxoid binding sites. Nat. Chem. Biol. 2006, 3, 117–125.
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