Organoboronic acids/esters as effective drug and prodrug candidates in cancer treatments: challenge and hope

Figures & data

Figure 1. The release mechanism of active prodrug from boron-masking using direct C–B bond oxidation/rearrangement strategy.

Figure 2. Some biological active organoboron derivatives in medicine.

Table 1. The safety profile of Velcade® and Ninlaro®.

Toxicity/side effect	Bortezomib (VELCADE®)	Ixazomib (NINLARO®)	Managing the side effect	Reference
Peripheral neuropathy	Grade ≥ 2, 24–39% Grade ≥ 3, 6–15%)	Grade 1 (18%) Grade 2 (11%) Grade 3 (2%)	Monitor the symptoms, decrease the dose or decrease the dose-intense schedule	^58
Thrombocytopenia	Grade 3 (35%) Grade 4 (43%) Severe (30%)	Grade 3 (13%) Grade 4 (17%)	Monitor blood count regularly and adjust dosing accordingly	^59
Cardiac toxicity	≤1%	No significant cardiovascular risk	Monitor patients with existing heart diseases	^60
Gastrointestinal toxicity (diarrhoea, nausea, and vomiting)	Diarrhoea (55–58%, severe 7–8%) Nausea (57–64%, severe 2–7%) Vomiting (35–36%, severe 3–7%)	All grades: Diarrhoea (52%) Nausea (32%) Vomiting (26%) Severe (2–3%)	Use of antiemetic and antidiarrheal medications or fluid replacement	^57–59
Hepatotoxicity	≤1%	≤1%	Monitor hepatic enzymes	^60

Table 2. Health-promoting anticancer activities of the organoboronic acids/esters drugs and prodrugs.

Drugs/prodrugs/ compound no	Commercial/ abbreviated name	Status	Year of approval/ clinical trials	Cancer type/ type of cell lines	Type of medication/dose	Mechanism of action	Reference
Bortezomib/1	Velcade®	Approved	FDA in 2003/Health Canada in 2008	Multiple myeloma	Injectable medication/1.3 mg/m²	20S Proteasome inhibitor/CT-L inhibitor	^40^,^41^,^43^,^45^,^62
Ixazomib/2	Ninlaro®	Approved	FDA in 2015/Health Canada in 2016	Multiple myeloma	Oral medication/2.3 mg, 3 mg or 4 mg	20S proteasome inhibitor/CT-L, T-L and C-L inhibitor	^44–46^,^52^,^62
Talabostat/11	PT-100/Val-Boro-Pro	Failed phase III clinical trials	2006	Non-Hodgkins lymphoma, leukaemia, melanoma, lung and pancreatic cancers	Oral medication/300 µg	DPP and FAP inhibitor	^62^,^63^,^77
Delanzomib/12	CEP-18769	Passed phase I but failed phase II clinical trials	2013	Solid tumours, MM, non-Hodgkins lymphoma	Oral medication/1.5 mg	Proteasome and NF-KB α inhibitor	^67^,^78
13	Boronic acid derivative	Currently under pre-clinical trials	NA	lung (cell lines: A549, 95D), colon (cell line: HCT116), leukaemia (cell line: MGC803), gastric (cell line: MGC803, MKN45), hepatoma (cell line: BEL7404), ovarian (cell line: SKOV3), breast (cell line: MDA-MB-231), liver (HepG2), and pancreatic cancer (cell line: SW1990)	Tested over six concentrations based on three experiments (refer to the reference for more details)	Proteasome inhibitor	^69
14	Boronic ester derivative	pre-clinical trials	NA	In vitro, in silico, and in cellulo showed low nanomolar activities similar to bortezomib and ixazomib. In vivo: great results of tumour necrosis on mice assays with TNBC	NA	NA	^70^,^71
15	Peptide boronate derivative	Pre-clinical trials	NA	Multiple myeloma (cell lines: RPMI-8226, U266 and KM3/BTZ)	NA	Proteasome inhibitor/HDAC inhibitor	^72
16	Boronic acid derivative	Pre-clinical trials	NA	Leukaemia	NA	dCTPase inhibitor	^74
17	MIDA-boronate ester	Pre-clinical trials	NA	Leukaemia	NA	dCTPase inhibitor	^74
18	Benzoxaborate derivative	Pre-clinical trials	NA	Ovarian cancer	NA	Proteasome inhibitor	^75
19	Boron pinacolate derivative	Pre-clinical trials	NA	Breast cancer	NA	A prodrug of endoxifen	^76
Boronphenylalanine/20	BPA	Approved	2012	Breast, bone, head, and neck cancers	Injectable medication/200 mg/kg	Upregulate LAT-1 expression	^79–83
Sodium boroncaptate/21 boronphenylalanine-fructose/22	BSH/BPA-F	Approved	2007	Thyroid, head, and neck cancers, and liver metastases	Injectable medication/BPA-F 900 mg/kg and BSH 100 mg/kg	Upregulate LAT-1 expression	^79–83
Calcium fructoborate (CF)/23	Borate derivative	Pre-clinical trials	NA	Prostate, lung, cervical, and breast cancer (cell line: MDA-MB-231)	IC50 = 5 mM	Inhibits superoxide, interleukin-1β, interleukin-6 and nitric oxide release.	^84^,^85
Boronate belinostat/24	Boron pinacolate derivative	Pre-clinical trials	NA	Breast, lung and cervical cancer (cell lines: MDA-MB-231, MCF-7, A549, and HeLa)	IC50 =10–50 µM	Inhibits the mentioned cell lines	^75^,^86
Boronate 5-fluorouracil/25	Boronic acid and boron pinacolate derivatives	Pre-clinical trials	NA	Breast cancer (cell lines: MCF-7, MDA-MB-468, OVCAR-3)	IC50 =50 µM	Inhibits the mentioned cell lines	^86
Boronate doxorubicin/26	Boron pinacolate derivative	Pre-clinical trials	NA	Cervical cancer (cell line: HeLa), and breast cancer (cell lines: 4T1 MDF-7)	IC50 =0.3 µM	Inhibits the mentioned cell lines	^76^,^87
Boronate diethyldithiocarbamate/27	Boron pinacolate derivative	Pre-clinical trials	NA	Breast cancer (cell line: 4T1)	IC50 = <100 mM	Inhibits cancer cell line 4T1 in vivo and in vitro	^88
Boronate chlormethine/28	Boronic acid and boron pinacolate derivatives	Pre-clinical trials	NA	Leukaemia (cell line: SR), lung cancer (cell line NCI-H460)	IC50 =10 µM	Inhibits the mentioned cell lines	^16^,^18^,^89
Benzyloxycarbonyl crizotinib/29	Boronic acid derivative	Pre-clinical trials	NA	Lung cancer (cell line H2228) and cell line RUMH	IC50 =3–15 µM	Inhibits the mentioned cell lines	^90^,^91
Boronated theranostic/30	Boron pinacolate derivative	Pre-clinical trials	NA	Cervical cancer (cell line: HeLa)	IC50 =30 µM	Inhibits the HeLa cell line	^92
Decaboranate phenoxyacetanilide/31	Decaborane derivative	Pre-clinical trials	NA	Colon and cervical cancer (cell line: HeLa)	IC50= 0.74-µM (cervical)/IC50= 5 µM (colon)	IC50 and GI50 inhibition	^93

Notes: FDA: Food and Drug Administration; CT-L: chymotrypsin-like; T-L: trypsin-like; C-L: caspase-like; FAP: fibroblast activation protein-alpha; DPP: dipeptidyl peptidase; MM: multiple myeloma; NF-KB α: nuclear factor kappa B alpha; TNBC: triple-negative breast cancer; MIDA: N-Methylimidodiacetic; HDAC: histone deacetylase; dCTPase: deoxycytidine triphosphatase; BPA: boronophenylalanine; LAT-1: large neutral amino acid transporter; GI₅₀: half maximal growth inhibitory concentration; IC₅₀: half maximal inhibitory concentration.

Figure 3. Organoboron derivatives in breast, lung, cervical, and colon cancer treatments.

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