2H-chromene and 7H-furo-chromene derivatives selectively inhibit tumour associated human carbonic anhydrase IX and XII isoforms

Figures & data

Figure 1. Examples of 2H-chromene and 7H-furo-chromene-based potential anticancer derivatives^51,52,54,55 and newly synthesised chromene series.

Figure 2. Structure and substitution pattern of 2H-chromene EMAC10163a-k and 7H-furo-chromene EMAC10164a-d, g-k.

Scheme 1. Synthetic pathway to obtain compounds EMAC10163a-k and EMAC10164a-d, g-k. Reagents, and conditions: (i) dimethyl 2-acetylsuccinate, H₂SO₄ 98%; (ii) acetone, K₂CO₃, α-haloketone, reflux, 6–24 h; (iii) propan-2-ol, NaOH, reflux 2–5 h.

Table 1. Inhibition data towards hCA I, II, IX, and XII of EMAC10163a-k and EMAC10164a-d, g-k.

Compound	R	Ki (µM)
		hCA I		hCA II	hCA IX	hCA XII
EMAC10163a	4′-CH3	>100		>100	2.98	2.52
EMAC10163b	4′-OCH3	>100		>100	0.53	0.47
EMAC10163c	4′-Br	>100		>100	4.16	5.43
EMAC10163d	4′-F	>100		>100	2.39	6.04
EMAC10163e	4′-NO2	>100		>100	4.64	7.84
EMAC10163f	3′- NO2	>100		>100	>100	7.82
EMAC10163g	4′-C6H5	>100		>100	>100	8.88
EMAC10163h	2′,4′-F	>100		>100	4.51	5.56
EMAC10163i	H	>100		>100	>100	5.25
EMAC10163j	4′-Cl	>100		>100	>100	2.41
EMAC10163k	3′-OCH3	>100		>100	>100	4.86
EMAC10164a	4′-CH3	>100		>100	>100	4.09
EMAC10164b	4′-O CH3	>100		>100	>100	4.59
EMAC10164c	4′-Br	>100		>100	>100	4.44
EMAC10164d	4′-F	>100		>100	0.46	0.80
EMAC10164g	4′-C6H5	>100		>100	0.71	0.82
EMAC10164h	2′,4′-F	>100		>100	4.27	6.37
EMAC10164i	H	>100		>100	3.18	3.38
EMAC10164j	4′-Cl	>100		>100	3.22	7.86
EMAC10164k	3′-OCH3	>100		>100	4.16	3.66
AAZ		0.250		0.0125	0.026	0.0057

Figure 3. Representation of the putative binding mode of the EMAC10163a and EMAC10163b compounds obtained by docking experiments in complex with hCA IX. (A) 3D representation of EMAC10163a and its respective interactions with CA IX residues; (B) 2D depiction of interactions; (C) 3D depiction of EMAC10163a and its respective interactions with CA IX residues considering a different orientation of the compound; (D) 2D depiction of interactions; (E) 3D depiction of EMAC10163b and its respective interactions with CA IX residues; (F) 2D depiction of interactions; (G) 3D depiction of EMAC10163b and its respective interactions with CA IX residues considering a different orientation of the compound; (H) 2D depiction of interactions.

Figure 4. Representation of the putative binding mode of the EMAC10164 series most potent compounds obtained by docking experiments in complex with hCA IX. (A) 3D depiction of EMAC10164d and its respective interactions with CA IX residues; (B) 2D depiction of interactions; (C) 3D depiction of EMAC10164g and its respective interactions with CA IX residues; (D) 2D depiction of interactions.

Figure 5. Representation of the putative binding mode of the most potent compounds from EMAC10163-open form series obtained by docking experiments in complex with hCA IX. (A) 3D depiction of EMAC10163a-open-E and its respective interactions with CA IX residues; (B) 2D depiction of interactions; (C) 3D depiction of EMAC10163a-open-Z and its respective interactions with CA IX residues; (D) 2D depiction of interactions; (E) 3D depiction of EMAC10163b-open-E and its respective interactions with CA IX residues; (F) 2D depiction of interactions; (G) 3D depiction of EMAC10163b-open-Z and its respective interactions with CA IX residues; (H) 2D depiction of interactions.

Figure 6. Representation of the putative binding mode of the EMAC10163 series most potent compounds obtained by docking experiments in complex with hCA XII. (A) 3D depiction of EMAC10163a and its respective interactions with CA XII residues; (B) 2D depiction of interactions; (C) 3D depiction of EMAC10163b and its respective interactions with CA XII residues; (D) 2D depiction of interactions; (E) 3D depiction of EMAC10164b and its respective interactions with CA XII residues considering a different orientation of the compound; (F) 2D depiction of interactions.

Figure 7. Representation of the putative binding mode of the EMAC10164 series most potent compounds obtained by docking experiments in complex with hCA XII. (A) 3D depiction of EMAC10164d and its respective interactions with CA XII residues; (B) 2D depiction of interactions; (C) 3D depiction of EMAC10164g and its respective interactions with CA XII residues; (D) 2D depiction of interactions.

Melis C, Distinto S, Bianco G, Meleddu R, Cottiglia F, Fois B, Taverna D, Angius R, Alcaro S, Ortuso F, et al. Targeting tumor associated carbonic anhydrases IX and XII: highly isozyme selective coumarin and psoralen inhibitors. ACS Med Chem Lett. 2018;9(7):725–729.

 PubMed Web of Science ®Google Scholar

Meleddu R, Deplano S, Maccioni E, Ortuso F, Cottiglia F, Secci D, Onali A, Sanna E, Angeli A, Angius R, et al. Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives. J Enzyme Inhib Med Chem. 2021;36(1):685–692.

 PubMed Web of Science ®Google Scholar

Park H, Choe H, Hong S. Virtual screening and biochemical evaluation to identify new inhibitors of mammalian target of rapamycin (mTOR). Bioorg Med Chem Lett. 2014;24(3):835–838.

 PubMed Web of Science ®Google Scholar

Mi C, Ma J, Wang KS, Zuo HX, Wang Z, Li MY, Piao LX, Xu GH, Li X, Quan ZS, et al. Imperatorin suppresses proliferation and angiogenesis of human colon cancer cell by targeting HIF-1α via the mTOR/p70S6K/4E-BP1 and MAPK pathways. J Ethnopharmacol. 2017;203:27–38.

 PubMed Web of Science ®Google Scholar