CN1242369A - Binuclear aromatic, heterocyclic monoacyl hydroxamic acid dialkyl-tin compounds, and method for synthesizing same - Google Patents

Abstract

The present invention relates to a binuclear aromatic heterocyclic monoacyl hydroxamic acid dialkyl tin compound, its structural general formula and its synthesizing method. Under the condition of low dose (0.00000001 mol/L) it possesses broad-spectrum, low-toxicity and strong anti-cancer activity.

Description

Dialkyl tin compound of binuclear aromatic heterocyclic monoacyl hydroxamate and its synthesis

The invention relates to an organotin compound with anticancer activity and a synthesis method thereof.

Gielen et al synthesized a series of polynuclear substituted dihydrocarbyltin benzoate compounds { [ RR' SnOOCR "]₂O}₂(see the literature appl. organomet. chem., 1991, 5, 497-506.; 1993, 7, 119-125.; 1993, 7, 201-206.), generally has better in vitro anti-MCF-7 (breast cancer) and WiDr (colon cancer) activity than Cisplatin (Cisplatin), but the anti-cancer activity is limited because the compound is too toxic.

The aim of the invention is to develop a series of medicines at low doses (10)^-8mol/L) of the organic tin compound has broad spectrum, low toxicity and strong anticancer activity.

The synthesized binuclear aromatic heterocyclic monohydroyl hydroxamic acid dialkyl tin compound [ R₂”Sn(OR’NOCR)]₂O17 species, up to hundreds being synthesized and ready for synthesis. The structural general formula of the complex is confirmed by element analysis, infrared spectrum and nuclear magnetic resonance hydrogen spectrum:

wherein, R ═ Et, Bu, Ph, and the like; r' ═ H, Ph, etc.;

and the like, and benzene rings substituted at various positions with halogen (F, Cl, Br, I), nitro, amino, hydroxyl, alkyl, alkoxy, and the like. (some of the compounds are shown in Table 1)1. synthetic route (the synthetic route in Table 1 is as follows:)

[3]2. Preparation method (Each route of the synthetic routes was performed as follows)<1>]a：

0.2 mol of the acid RCOOH is dissolved in 2 mol of methanol CH₃OH or 1.334 mol of absolute ethanol C₂H₅In OH, cooling in an ice-water bath, slowly dripping 16.7 ml of concentrated sulfuric acid while stirring, and refluxing for 4 hours. Cooled to 30 ℃, adjusted to PH 9 with 20% sodium carbonate solution, extracted with anhydrous ether, the combined extracts, dried ether extracts over anhydrous magnesium sulfate, shaken and allowed to stand overnight. Filtering to remove desiccant, evaporating the filtrate with rotary evaporator to remove diethyl ether and excessive alcohol, and collecting the rest fraction by vacuum distillation to obtain ester RCOOR. Route [1]b：

0.1 mol of the acid RCOOH is dissolved in 0.8 mol of absolute ethanol C₂H₅In OH, cooling in ice water bath, slowly dripping 7 ml of concentrated sulfuric acid while stirring, and refluxing for 6 hours. Cooling to 30 deg.C, adjusting pH to 9 with 20% sodium hydroxide solution, extracting with toluene, mixing extractive solutions, and adding anhydrous sulfurThe toluene extract was dried over magnesium, shaken and allowed to stand overnight. Filtering to remove desiccant, evaporating the filtrate with rotary evaporator to remove toluene and excessive alcohol, and collecting the rest by vacuum distillation to obtain ester RCOOR (RCOOC)₂H₅)。

TABLE 1 synthetic route assignments for the class of compounds synthesized

Note: the abbreviated ligands in the table correspond to the names as follows:

BHA ═ Benzohydroxamic acid, benzoyl hydroxamic acid;

SHA ═ Salicylhydroxamic acid, Salicylhydroxamic acid;

PHBHA ═ p-Hydroxybenzohydroxamic acid, p-hydroxybenzoyl hydroxamic acid;

CiHA ═ cinnamyl hydroxamic acid;

N-Phenyl benzoyl hydroxamic acid, N-Phenyl benzoyl hydroxamic acid;

ONBHA o-nitrobenzoylhydroxamic acid, o-nitrobenzoyl hydroxamic acid;

MNBHA m-nitrobenzoylhydroxamic acid, m-nitrobenzoyl hydroxamic acid;

PNBHA ═ p-nitrobenzoylhydroxamic acid, p-nitrobenzoyl hydroxamic acid;

OABHA o-Aminobenzohydroxamic acid, anthranoylhydroxamic acid;

m-Aminobenzohydroxamic acid, m-aminobenzoyl hydroxamic acid;

PABHA ═ p-Aminobenzohydroxamic acid, p-aminobenzoyl hydroxamic acid;

FuHA ═ Furan-2-carbohydroxamic acid, furoyl hydroxamic acid;

niaa (Nicotinohydroxamic acid);

isa (Isonicotinohydroxamic acid). Route [2]a:

24.32 g (0.35 mol) of hydroxylamine hydrochloride were dissolved in 140 ml of methanol by reflux, and 30.86 g (0.55 mol) of potassium hydroxide were dissolved in 100 ml of methanol by the same method. And when the solution and the solution are cooled to 30-40 ℃, pouring the rear solution into the front solution while cooling and shaking, standing for 5 minutes to ensure that the potassium chloride is completely precipitated, and filtering out the precipitate to obtain a methanol solution of hydroxylamine and potassium hydroxide. Adding 0.2 mol of the prepared ester RCOOR _ into the filtrate, stirring for 2 hours to obtain RCONHOK precipitate, filtering, dissolving in a small amount of water, stirring, acidifying with 2N acetic acid to pH 5, stirring for 2 hours, filtering to obtain a crude product, recrystallizing with water twice, and vacuum drying to obtain ligand RCONHOH. Route [2]b:

19.6 g (0.49 mol) of sodium hydroxide was dissolved in 80 ml of water, and slowly added to 100 ml of ice water containing 15.8 g (0.1 mol) of hydroxylamine sulfate, and 0.1 mol of ester RCOOR. RTM. was added. Stir at room temperature under nitrogen for 4 hours overnight. Acidification with 25% sulfuric acid in anice bath resulted in precipitation. Filtering, recrystallizing twice with water, and vacuum drying to obtain ligand hydroxamic acid RCONHOH. Route [3]:

4 mmol of ligand hydroxamic acid RCONHOH is dissolved in a mixture of 120 ml of toluene and 40 ml of absolute ethanol (or 200 ml of a mixture of 3: 1 benzene: methanol) by reflux, and then 4 mmol of tin dihydrocarbyloxide R is added₂"SnO, refluxing for 6 hours. After the reaction is finished, evaporating a half of the solvent, evaporating the rest under the evacuation state to obtain a crude product, recrystallizing by using absolute ethyl alcohol, filtering, collecting, and drying in vacuum to obtain the binuclear aromatic and heterocyclic monoacyl hydroxamic acid dialkyl tin compound [ R [₂”Sn(OR’NOCR)]₂O (when R ═ substituent is-OH, -NH)₂The benzene ring of (a), the whole reaction process needs to be protected by nitrogen).

The elemental analysis and physical property data of the ligand RCONR' OH and the complex are shown in Table 2, the infrared spectrum data are shown in Table 3, and the nuclear magnetic hydrogen spectrum data are shown in Table 4. 3. The apparatus used for the experiment: a digital melting point instrument produced by Shanghai physical optical instrument factories; 240C elemental analyzer and Vario EL type elemental analyzer; shimadzu IR-435 infrared spectrometer and Perkin-Elmer-983 infrared spectrometer;¹h NMR is measured by a Bruker DRX300MHZ nuclear magnetic resonance instrument and a Bruker AM-500MHZ nuclear magnetic resonance instrument, TMS is used as an internal standard, and deuterated DMSO and deuterated chloroform are used as solvents; molecular weightThe solvent is naphthalene as determined by freezing point depression.

TABLE 2 elemental analysis and physical Property data for ligands and complexes

Compound (I)	Molecular weight	Appearance of the product	mp/℃	Yield of	Elemental analysis/% found (calculated)
								Mr	％	C	H	N
	BHA			137	White colour	128.7～129.7	65						61.52(61.31)	5.13(5.11)	10.38(10.22)
[(BHA)SnEt2]2O		642	White colour					272.0～273.7	75	47.05(47.17)	4.83(5.02)	4.80(4.36)
	[(BHA)SnBu2]2O			754	White colour	230.2～230.5	78						47.52(47.78)	6.15(6.42)	3.89(3.71)
SHA		153	White colour					177.3～179.0	60	54.75(54.90)	4.69(4.58)	8.97(9.15)
	[(SHA)SnEt2]2O			674	Light yellow	154.4～154.7	70						40.16(39.21)	4.50(4.79)	4.29(4.16)
[(SHA)SnBu2]2O		786	White colour					179.1～180.1	72	45.19(45.84)	6.05(6.15)	3.64(3.56)
	PHBHA			153	White colour	179.2～180.8	67						55.21(54.90)	4.56(4.58)	8.93(9.15)
[(PHBHA)SnEt2]2O		674	White colour					238.1～239.2	72	40.25(39.21)	4.38(4.79)	4.41(4.16)
	[(PHBHA)SnBu2]2O			786	Light brown	236.6～238.4	65						45.47(45.84)	6.11(6.15)	3.45(3.56)
CiHA		163	Shallow powder					97.4～99.3	80	66.07(66.26)	5.39(5.52)	8.70(8.59)
	[(CiHA)SnBu2]2O			806	White colour	203.0～204.2	88						50.50(50.62)	6.30(6.45)	3.53(3.47)
[(N-PhBHA)SnBu2]2O		906	Light yellow					197.8～199.7	93	55.82(55.63)	6.31(6.18)	2.98(3.09)
	ONBHA			182	White colour	148.0～149.3	25						46.81(46.15)	3.27(3.30)	14.78(15.38)
[(ONBHA)SnBu2]2O		844	Light yellow					168.3～170.0	68	41.99(42.65)	5.72(5.45)	6.47(6.63)
	MNBHA			182	White colour	153.4～154.9	60						46.49(46.15)	3.27(3.30)	15.47(15.38)
[(MNBHA)SnBu2]2O		844	Yellow colour					176.9～178.2	62	42.06(42.65)	5.19(5.45)	6.42(6.63)
	PNBHA			182	Light yellow	166.0～167.8	50						46.44(46.15)	3.29(3.30)	14.81(15.38)
[(PNBHA)SnBu2]2O		844	Deep yellow					178.3～180.0	67	42.06(42.65)	5.45(5.45)	6.48(6.63)
	OABHA			152	Shallow powder	146.7～148.0	54						55.08(55.26)	5.21(5.26)	18.32(18.42)
[(OABHA)SnBu2]2O		784	White colour					＞300	71	45.80(45.92)	6.20(6.38)	7.03(7.14)
	MABHA			152	White colour	153.4～154.8	60						55.38(55.26)	5.09(5.26)	18.38(18.42)
[(MABHA)SnBu2]2O		784	White colour					＞300	75	46.09(45.92)	6.52(6.38)	7.34(7.14)
	PABHA			152	Shallow powder	169.9～170.3	85						55.23(55.26)	5.16(5.26)	18.30(18.42)
[(PABHA)SnBu2]2O		784	Golden yellow					133.8～135.0	87	45.88(45.92)	6.58(6.38)	7.28(7.14)

FuHA	127	White colour	119.9～121.6	63	47.14(47.24)	3.83(3.94)	10.89(11.02)
								[(FuHA)SnBu2]2O	734	Yellow colour	97.5～99.3	82	42.71(42.51)	5.87(5.99)	3.66(3.81)
NiHA	138	White colour	161.4～161.9	61	52.35(52.17)	4.25(4.34)	20.18(20.29)
								[(NiHA)SnBu2]2O	756	White colour	207.6～208.0	79	44.30(44.44)	6.13(6.08)	7.22(7.41)
IsHA	138	White colour	160.6～160.9	65	52.30(52.17)	4.36(4.34)	20.32(20.29)
								[(IsHA)SnBu2]2O	756	Light yellow	201.2～203.0	86	44.28(44.44)	6.20(6.08)	7.53(7.41)

TABLE 3 Infrared Spectroscopy data (v.cm) for ligands and complexes^-1)

Compound (I)	νNH-OH	νC＝O	νN-O	νSn-C	νSn-O	νSn-O-Sn
							BHA	3060～2900	1650	895	----	----	----
[(BHA)SnEt2]2O	3424	1579 1546	959 928	530	495	614
							[(BHA)SnBu2]2O	3423	1594 1555	961 925	528	479	611
SHA	3380～2700	1640	910	----	----	----
							[(SHA)SnEt2]2O	3430	1597 1544	955 922	585	498	667
[(SHA)SnBu2]2O	3415	1596 1545	948 937	588	490	647
							PHBHA	3270～2675	1650	908	----	----	----
[(PHBHA)SnEt2]2O	3254	1579 1569	957 914	532	494	653
							[(PHBHA)SnBu2]2O	3267	1598	915	570	440	610
CiHA	3230～2600	1650	980	----	----	----
							[(CiHA)SnBu2]2O	----	1570	990	554	461	614
N-PhBHA	3150～2900	1620	908	----	----	----
							[(N-PhBHA)SnBu2]2O	----	1543	920	532	492	564
ONBHA	3220～3010	1650	890	----	----	----
							[(ONBHA)SnBu2]2O	3400	1590	950
MNBHA	3350～3200	1640	890	----	----	----
							[(MNBHA)SnBu2]2O	3400	1580	920
PNBHA	3250～2800	1650	890	----	----	----
							[(PNBHA)SnBu2]2O	----	1560	920
OABHA	3250～2800	1650	890	----	----	----
							[(OABHA)SnBu2]2O	----	1575	908	561	463	631
MABHA	3250～2780	1645	890	----	----	----
							[(MABHA)SnBu2]2O	----	1580	910	538	469	637
PABHA	3250～2790	1640	890	----	----	----
							[(PABHA)SnBu2]2O	----	1620	906	524	470	614
FuHA	3300～2500	1630	935	----	----	----
							[(FuHA)SnBu2]2O	----	1580	947	587	463	607
NiHA	3160 2800～2500	1640	900	----	----	----
							[(NiHA)SnBu2]2O	----	1535	910	516	460	610
IsHA	3200～2500	1635	900	----	----	----
							[(IsHA)SnBu2]2O	----	1565	920	529	495	608

4. Structural characterization (1) Infrared Spectroscopy

As can be seen from table 3: the infrared spectrum of the ligand RCONR' OH is 3380-2500 cm^-1The range of the absorption peak of the hydroxyl stretching vibration is 1620-1650 cm^-1A carbonyl absorption peak appeared. When the ligand forms a complex, the hydroxyl absorption peak disappears, showing that the deprotonation of the hydroxyl and the coordination of the oxygen atom thereof are shown, and the carbonyl absorption peak is red-shifted to 1535-1597 cm^-1The carbonyl oxygen is illustrated as forming a coordinate bond with metallic tin. V in the complex_N-HShifting to high frequency 3400cm^-1The coordination of nitrogen atoms in NHOH groups and tin is eliminated, and the tin belongs to hard acid, so that the soft and hard acid-base rules are met. V of the partial Complex_N-HDisappearance, probably because the active hydrogen on the nitrogen atom in the partial ligand is transferred to the oxygen atom and exists in the form of HO-C ═ N-OH, and the oxygen atom is dehydrogenated and then coordinated with tin, so 3300cm is not observed in the complex^-1V around_N-HPeak(s). The coordinated N-O stretching vibration absorption peak generally moves to high frequency by delta v 10-66 cm^-1And the absorption strength is increased, which on the one hand excludes coordination of nitrogen atoms in NH-OH groups,on the other hand, it is also proved that the oxygen in NH-OH coordinates with tin. Only v is observed in the IR spectrum of the complex_Sn-OAbsorption peak, with no actual observation of v_Sn-NAbsorption peak, about 415cm^-1To (3). In the complexes, the concentration of the complex is observed to be 610-667 cm^-1Internal strong peak, which is v_Sn-O-SnThe element analysis and the guess result are matched.

The above IR parameters indicate that the ligand is chelated to tin with the oxygen atom in the CO — NHOH (or HO-C ═ N-OH) group. Only one v was observed in the complex_Sn-CIndicating that the two hydrocarbon radicals R' are in the trans position.

TABLE 4 nuclear magnetic hydrogen of ligands and complexesSpectral data (delta ppm)

Compound (I)	Ring (C)	CH3	CH2	(CH2)nSn	-NHOH(-NHO-)
						BHA	7.49～7.89(5H)	----	----	----	10.21(2H)
[(BHA)SnEt2]2O	7.30～7.75(10H)	1.19(12H)	----	1.37(8H)	9.80(2H)
						[(BHA)SnBu2]2O	7.31～7.72(10H)	0.83(12H)	1.30(8H)	1.58(16H)	9.87(2H)
SHA	6.99～7.31(4H)	----	----	----	unobserved
						[(SHA)SnEt2]2O	6.67～7.71(8H)	1.11(12H)	----	1.35(8H)	8.69(2H)
[(SHA)SnBu2]2O	6.77～7.80(8H)	0.81(12H)	1.33(8H)	1.42(16H)	8.79(2H)
						PHBHA	6.97～7.82(4H)	----	----	----	9.53(1H)8.70(1H)
[(PHBHA)SnEt2]2O	6.78～7.79(8H)	1.18(12H)	----	1.28(8H)	8.44(2H)
						[(PHBHA)SnBu2]2O	6.75～7.74(8H)	0.85(12H)	1.31(8H)	1.54(16H)	8.46(2H)
CiHA	6.47-7.56(7H) Ph-CH＝CH-	----	----	----	unobserved
						[(CiHA)SnBu2]2O	6.43～7.50(4H)	0.87(12H)	1.27(16H)	1.49(8H)	----
N-PhBHA	7.16～7.63(10H)	----	----	----	10.72(1H)
						[(N-PhBHA)SnBu2]2O	7.19～7.36(20H)	0.93(12H)	1.48(8H)	1.76(16H)	----
ONBHA	7.90～8.67(4H)	----	----	----	11.67(1H)9.37(1H)
						[(ONBHA)SnBu2]2O	7.68～7.88(8H)	1.01(12H)	1.44(8H)	1.72(16H)	----
MNBHA	7.91～8.71(4H)	----	----	----	11.76(1H)9.51(1H)
						[(MNBHA)SnBu2]2O	7.80～8.73(8H)	1.00(12H)	1.45(8H)	1.73(16H)	----
PNBHA	8.14～8.48(4H)	----	----	----	11.74(1H)9.51(1H)
						[(PNBHA)SnBu2]2O	8.10～8.32(8H)	1.00(12H)	1.45(8H)	1.70(16H)	----
OABHA	6.47～7.28(4H)	----	----	----	10.16(1H)8.80(1H)
						[(OABHA)SnBu2]2O	6.52～7.32(8H)	0.89(12H)	1.37(8H)	1.61(16H)	----
MABHA	6.64～7.04(4H)	----	----	----	10.94(1H)8.85(1H)
						[(MABHA)SnBu2]2O	6.63～7.17(8H)	0.89(12H)	1.38(8H)	1.61(16H)	----
PABHA	6.53～7.45(4H)	----	----	----	10.71(1H)8.64(1H)
						[(PABHA)SnBu2]2O	6.61～7.51(8H)	0.87(12H)	1.35(8H)	1.63(16H)	----
FuHA	6.55～7.75(3H)	----	----	----	11.10(1H)9.06(1H)
						[(FuHA)SnBu2]2O	6.58～7.64(6H)	0.83(12H)	1.29(8H)	1.52(16H)	----
NiHA	7.50～8.90(4H)	----	----	----	11.39(1H)9.22(1H)
						[(NiHA)SnBu2]2O	7.33～8.87(8H)	0.81(12H)	1.28(8H)	1.54(16H)	----
IsHA	7.65～8.69(4H)	----	----	----	11.50(1H)9.30(1H)
						[(IsHA)SnBu2]2O	7.69～8.78(8H)	0.91(12H)	1.41(8H)	1.69(16H)	----

(2)：¹H NMR (nuclear magnetic hydrogen Spectroscopy) analysis

As can be seen from table 4: the absorption peak of benzene ring or heterocyclic ring proton in all complexes is obviously changed compared with that of free ligand, which is caused by the induction effect after the ligand is coordinated with tin.

The ligand has two protons respectively in the range of 9.53-11.76 and 8.64-9.53 before coordination, which are respectively assigned to OH and NH of NH-OH, but in the complex, the OH proton peak of NH-OH has disappeared, which proves that the coordination of deprotonation of hydroxyl in NH-OH and oxygen is consistent with the speculation of IR spectrum. After BHA, SHA and PHBHA are coordinated, NH peak of NH-OH still exists, on one hand, coordination of nitrogen atoms in NH-OH groups is eliminated, and on the other hand, coordination of oxygen in NH-OH and tin is also proved. The proton on the nitrogen of the complex does not generate an absorption signal and can be related to the rapid exchange of active hydrogen, the active hydrogen on the nitrogen atom in the ligand is transferred to an oxygen atom and exists in the form of HO-C ═ N-OH, and the oxygen atom is coordinated with tin after being dehydrogenated, so that no absorption signal is observed in the complexThe NH proton peak was observed. Therefore, the temperature of the molten metal is controlled,¹h NMR results also demonstrate the presumption that the ligand is coordinated to the tin chelate by the oxygen atom in the CO — NHOH (or HO-C ═ N-OH) group. In addition, hydrocarbyl R 'appears as a multiplet, also indicating that R' is in a non-linear inversion.

In combination with the above-mentioned IR,¹h NMR, elemental analysis and other parameters, the compound can be considered to be a pentacoordinate oxygen bridged binuclear triangular bipyramid structure. The anticancer activity of the compound (shown as the general formula)

The compounds are subjected to activity screening by the Beijing medical university natural medicine and bionic medicine national key laboratories (tables 5, 6, 7A, 7B, 8A and 8B) and the Shanghai pharmaceutical institute New drug screening national key laboratories (tables 9 and 10) of Chinese academy of sciences, and are found to have potent activity.

TABLE 5 median inhibitory concentration IC of the complexes on four human tumor cells₅₀(umol/L)

Compound (I)	Human nasopharyngeal carcinoma KB	Human leukemia HL-60	Human colon cancer HCT-8	Ehrlich ascites Ehrlich ascite
					[(BHA)SnEt2]2O	Is inactive	2.21	2.81	4.52
[(BHA)SnBu2]2O	0.98	1.54	1.26	0.24
					[(SHA)SnEt2]2O	1.00	0.87	2.75	0.35
[(PHBHA)SnEt2]2O	0.99	0.51	0.11	0.29
					[(PHBHA)SnBu2]2O	0.25	0.34	0.49	0.16

TABLE 6 inhibition of tumor cell growth by different concentrations of the complex%

Compound (I)	P388	A549	SGC
				1.0μM 10μM 100μM	1.0μM 10μM 100μM	1.0μM 10μM 100μM
	[(BHA)SnEt2]2O	54.4 98.1 100	59.6 95.7 97.9				38 85.2 86.1
[(BHA)SnBu2]2O				100 100 100	36.7 94.9 94.9	0 55.6 93.3
	[(SHA)SnEt2]2O	97.3 98.2 100	62.8 91.9 95.7				33.3 88.8 83.8
[(PHBHA)SnEt2]2O				100 100 100	66 95.7 99.7	40.7 88.9 95.4
	[(PHBHA)SnBu2]2O	97.1 100 100	69.4 92.4 94.4				0 91.1 95.1

Tables 7A to 7B, tables 8A to 8B, evaluation of results: -ineffective + less effective + + significant + + + more effective

TABLE 7 inhibition of tumor cell growth by different concentrations of the complexes%

Compound (I)	Testing Serial number	K562 *	Bel--7402*
				0.1. mu.M 1. mu.M 10. mu.M evaluation	0.1. mu.M 1. mu.M 10. mu.M evaluation
		[(BHA)SnEt2]2O	12			74.71 77.67 78.94 +++	9.20 12.08 79.27 +
[(BHA)SnBu2]2O	8			16.07 30.36 79.26 +	10.15 60.49 90.05 ++
		[(SHA)SnEt2]2O	13			65.06 83.16 85.30 +++	- 31.65 97.25 +
[(PHBHA)SnEt2]2O	14			16.96 22.63 47.26 -	77.82 95.74 98.59 +++
		[(PHBHA)SnBu2]2O	7			59.26 65.70 75.03 +++	13.82 65.11 93.17 ++

Note that^*: human erythroleukemia K₅₆₂Adopting a tetrazolium salt (MTT) colorimetric method;

human liver cancer Bel-7402 is stained with Sulfarhodamine (SRB) protein.

TABLE 7 inhibition of tumor cell growth by different concentrations of the complexes%

Testing Serial number	BGC*	KB*	HCT-8*
				0.1. mu.M 1. mu.M 10. mu.M evaluation	0.1. mu.M 1. mu.M 10. mu.M evaluation	0.1. mu.M 1. mu.M 10. mu.M evaluation
	12	-32.46 -19.43 48.10 -	19.97 13.74 45.11 -				11.27 6.37 97.94 +
8				10.02 23.97 81.26 +	32.14 53.12 90.74 ++	- 40.09 88.83 +
	13	-0.95 41.23 72.51 +	26.27 50.53 87.71 ++				- 10.13 98.46 +
14				39.10 59.72 86.97 ++	18.27 50.12 98.79 ++	68.38 95.71 97.67 +++
	7	-20.70 63.18 93.46 ++	27.03 65.41 93 76 ++				10.43 60.59 95.89 ++

Note that^*: human gastric cancer BGC (MTT method); human nasopharyngeal carcinoma KB (MTT method); human colon cancer HCT-8(SRB method)

TABLE 8 inhibition of tumor cell growth by different concentrations of the complexes%

Compound (I)	Testing Serial number	KB*	BGC-823*
				0.1. mu.M 1. mu.M 10. mu.M evaluation	0.1. mu.M 1. mu.M 10. mu.M evaluation
		[(CiHA)SnBu2]2O
[(N-PhBHA)SnBu2]2O	98203720			31.45 97.18 98.04 ++	-18.73 75.02 95.73 ++
		[(OABHA)SnBu2]2O	990072			Not determined	16.80 31.18 96.24 +
[(MABHA)SnBu2]2O	990074			-4.06 -1.42 35.53 -	2.54 -5.09 19.91 -
		[(PABHA)SnBu2]2O	98203680			80.00 98.03 97.92 +++	30.91 95.18 97.48 ++
[(FuHA)SnBu2]2O	98203620			49.30 94.76 98.18 ++	18.63 93.23 97.83 ++
		[(NiHA)SnBu2]2O	98203640			31.85 97.74 96.00 ++	21.91 94.13 97.55 ++
[(IsHA)SnBu2]2O	98203660			43.31 97.04 97.30 ++	21.49 93.57 97.41 ++

Note that^*: human nasopharyngeal carcinoma KB (SRB method); human gastric cancer BGC-823(SRB method).

TABLE 8 inhibition of tumor cell growth by different concentrations of the complexes%

Testing Serial number	Bel-7402*	HCT-8*	HL-60*
				0.1. mu.M 1. mu.M 10. mu.M evaluation	0.1. mu.M 1. mu.M 10. mu.M evaluation	0.1. mu.M 1. mu.M 10. mu.M evaluation
98203720				-9.44 61.72 94.46 ++	4.62 53.68 85.56 ++	-51.72 47.01 68.04 +
	990072	22.11 32.44 97.12 +	2.36 2.53 36.55 -				-14.65 4.49 77.60 +
990074				6.97 8.45 46.95 -	3.25 0.42 4.93 -	-5.35 -11.75 37.35 -
	98203680	33.81 92.10 95.77 ++	34.84 87.87 93.30 ++				-1.83 64.48 72.29 ++
98203620				41.71 86.87 95.21 ++	13.23 80.14 89.96 ++	37.26 64.46 88.27 ++
	98203640	40.60 91.10 94.99 ++	-21.78 72.41 86.02 ++				31.77 76.68 84.14 ++
98203660				29.81 87.98 95.88 ++	21.77 80.54 92.34 ++	-9.42 64.59 83.44 ++

Note that^*: human liver cancer Bel-7402(SRB method); human colon cancer HCT-8(SRB method); human leukemia HL-60(MTT method). The screening method comprises the following steps: tetrazolium salt (MTT) reduction cell line: p₃₈₈Action time of mouse leukemia: and (6 h) evaluating the result: and (4) invalidation: 10^-5mol/L＜85％；

Weak effect: 10^-5mol/L is more than or equal to 85 percent or 10^-6mol/L＞50％；

The strong effect is as follows: 10^-6mol/L is more than or equal to 85 percent or 10^-7mol/L＞50％；

TABLE 9 inhibition of tumor cell growth by different concentrations (mol/L) of the complex%

Compound (I)	Sample numbering	10-4 10-5 10-6 10-7 10-8Evaluation of
			[(CiHA)SnBu2]2O	1108	94.996.998.099.098.0 has strong therapeutic effect
[(N-PhBHA)SnBu2]2O	1091	80.093.892.571.363.8 has strong therapeutic effect
			[(ONBHA)SnBu2]2O	1034	84.557.152.450.048.8 has strong therapeutic effect
[(MNBHA)SnBu2]2O	1036	82.261.153.350.052.2 has strong therapeutic effect
			[(PNBHA)SnBu2]2O	1038	85.662.256.752.254.4 has strong therapeutic effect
[(OABHA)SnBu2]2O	1099	92.794.596.496.496.4 has strong therapeutic effect
			[(MABHA)SnBu2]2O	1101	84.690.490.490.490.4 has strong therapeutic effect
[(PABHA)SnBu2]2O	1087	92.596.386.365.058.8 has strong therapeutic effect
			[(FuHA)SnBu2]2O	1081	85.988.790.149.37.0 has strong therapeutic effect
[(NiHA)SnBu2]2O	1083	84.590.188.788.788.7 has strong therapeutic effect
			[(IsHA)SnBu2]2O	1085	84.590.190.190.190.1 has strong therapeutic effect

The screening method comprises the following steps: sulforhodamine B (SRB) protein staining method cell line: a-549 human lung adenocarcinoma action time: and (5) evaluating the result: and (4) invalidation: 10^-5mol/L＜85％；

Weak effect: 10^-5mol/L is more than or equal to 85 percent or 10^-6mol/L＞50％；

The strong effect is as follows: 10^-6mol/L is more than or equal to 85 percent or 10^-7mol/L＞50％；

TABLE 10 inhibition of tumor cell growth by different concentrations (mol/L) of the complex%

Compound (I)	Sample numbering	10-4 10-5 10-6 10-7 10-8Evaluation of
			[(CiHA)SnBu2]2O	1108	97.797.796.657.773.6 has strong therapeutic effect
[(N-PhBHA)SnBu2]2O	1091	94.892.791.791.789.6 has strong therapeutic effect
			[(ONBHA)SnBu2]2O	1034	85.172.489.787.482.8 has strong therapeutic effect
[(MNBHA)SnBu2]2O	1036	94.390.890.890.886.2 has strong therapeutic effect
			[(PNBHA)SnBu2]2O	1038	90.886.287.488.586.2 has strong therapeutic effect
[(OABHA)SnBu2]2O	1099	97.597.596.397.576.5 has strong therapeutic effect
			[(MABHA)SnBu2]2O	1101	96.595.397.695.322.4 has strong therapeutic effect
[(PABHA)SnBu2]2O	1087	92.791.791.790.684.4 has strong therapeutic effect
			[(FuHA)SnBu2]2O	1081	93.989.987.991.990.9 has strong therapeutic effect
[(NiHA)SnBu2]2O	1083	94.090.991.984.841.4 has strong therapeutic effect
			[(IsHA)SnBu2]2O	1085	92.990.990.991.961.6 has strong therapeutic effect

The screening method comprises the following steps: sulforhodamine B (SRB) protein staining method, tetrazolium salt (MTT) reduction method cell strain: HO-8910 human ovarian cancer, SPC-A4 human lung cancer, HCT-116 human colon cancer action time: 72h junctionAnd (4) fruit evaluation: and (4) invalidation: 10^-5mol/L＜85％；

Weak effect: 10^-5mol/L is more than or equal to 85 percent or 10^-6mol/L＞50％；

The strong effect is as follows: 10^-6mol/L is more than or equal to 85 percent or 10^-7mol/L＞50％；

TABLE 11 inhibition of tumor cell growth by cisplatin at various concentrations (mol/L)%

Cell line 10-4 10-5 10-6 10-7 10-8Evaluation of
	HO-891084.456.30.44.70.0 invalid SPC-A448.78.00.40.00.0 null HCT-11678.80.00.00.00.0 null

From the test results of tables 5 to 11, it can be seen that the series of organotin compounds of the present invention have broad spectrum, low toxicity and potent anticancer activity: (1) broad spectrum: the series of compounds can be used for treating human nasopharyngeal carcinoma KB, human gastric cancer BGC-823, human liver cancer Bel-7402, human colon cancer HCT-8, human leukemia HL-60, and human erythroleukemia K₅₆₂Ehrlich ascites, P₃₈₈Mouse leukemia, A-549 human lung adenocarcinomatumor cells and the like have stronger inhibitory power. (2) Low toxicity: taking Wish-human amniotic cells as an example, the SRB method is used, the action time is 72 hours, and the toxic concentration of the series of compounds to normal cells is 10^-6mol/L, inhibition concentration of 10 to tumor cells^-8The difference in mol/L is two orders of magnitude. (3) The strong effect is as follows: the series of compounds P₃₈₈The inhibition rate of mouse leukemia and A-549 human lung adenocarcinoma tumor cells is strong, and the traditional Chinese medicine composition is widely applied to clinical cis-lung adenocarcinoma tumor cellsThe platinum inhibition of HO-8910 human ovarian cancer, SPC-A4 human lung cancer, and HCT-116 human colon cancer was ineffective (see Table 11).

Example 1:

complex [ (FuHA) SnBu₂]₂O, structure is as described above, wherein

R' ═ H, R ═ Bu (1) synthetic route:

[3](2) the preparation method comprises the following steps: route [1]a: (Synthesis of furoic acid methyl ester)

22.4 g (0.2 mol) of furoic acid are dissolved in 64 g (2 mol, 80 ml) of methanol CH₃In OH, cooling in an ice-water bath, slowly dripping 16.7 ml of concentrated sulfuric acid while stirring, and refluxing for 4 hours. Cooled to 30 ℃, adjusted to PH 9 with 20% sodium carbonate solution, extracted with anhydrous ether, the combined extracts, dried ether extracts over anhydrous magnesium sulfate, shaken and allowed to stand overnight. Filtering to remove the drying agent, quickly evaporating diethyl ether and excessive alcohol from the orange filtrate by using a rotary evaporator, and collecting 86-86.5 ℃/30mmHg orange fraction from the rest by using reduced pressure distillation to obtain the methyl furoate with the yield of 62.3%. Route [2]a: (synthetic FuHA)

24.32 g (0.35 mol) of hydroxylamine hydrochloride were dissolved in 140 ml of methanol by reflux, and 30.86 g (0.55 mol) of potassium hydroxide were dissolved in 100 ml of methanol by the same method. And when the solution and the solution are cooled to 30-40 ℃, pouring the rear solution into the front solution while cooling and shaking, standing for 5 minutes to ensure that the potassium chloride is completely precipitated, and filtering out the precipitate to obtain a methanol solution of hydroxylamine and potassium hydroxide. Adding 24.66 g (0.2 mol, 21 ml) of prepared methyl furoate into the filtrate, stirring for 2 hours to obtain white precipitate of furoyl hydroxamic acid potassium salt, filtering, dissolving in a small amount of water, stirring, acidifying with 2N acetic acid until the pH is 5, stirring for 2 hours, filtering to obtain a crude product, recrystallizing twice with water, and drying in vacuum to obtain white ligand furoyl hydroxamic acid FuHA. Route [3]: (Synthesis of Complex [ (FuHA) SnBu₂]₂O)

0.5084 g (4 mmol) of FuHA ligand furoyl hydroxamate were dissolved in a mixture of 120 ml of toluene and 40 ml of absolute ethanol under reflux, and 0.996 g (4 mmol) of Bu dibutyl tin oxide was added₂SnO, reflux for six hours. After the reaction is finished, evaporating half of the solvent, evaporating the rest under the evacuation state to obtain a crude product, recrystallizing with absolute ethyl alcohol, filtering, collecting, and drying in vacuum to obtain the complex [ (FuHA) SnBu₂]₂And O. (3) The application is as follows:

the compound has strong inhibitory effect on human nasopharyngeal carcinomaKB, human gastric cancer BGC-823, human liver cancer Bel-7402, human colon cancer HCT-8, and human leukemia HL-60, and can be used for treating P₃₈₈The inhibition rate of mouse leukemia and A-549 human lung adenocarcinoma tumor cells is strong. Example 2:

complex [ (OABHA) SnBu₂]₂O, structure is as described above, wherein

R ═ H, R ═ Bu. (1) The synthetic route is as follows:

[3](2) the preparation method comprises the following steps: route [1]b: (Synthesis of Ethyl anthranilate)

13.71 g (0.1 mol) of anthranilic acid is dissolved in 36.8 g (0.8 mol, 46 ml) of absolute ethyl alcohol, cooled in an ice-water bath, slowly dropped into 7 ml of concentrated sulfuric acid under stirring, and heated and refluxed for 6 hours. Cooled to 30 ℃, adjusted to PH 9 with 20% sodium hydroxide solution, extracted with toluene, the extracts combined, the toluene extracts dried over anhydrous magnesium sulfate, shaken and left to stand overnight. Filtering to remove a drying agent, quickly evaporating toluene and excessive alcohol from the filtrate by using a rotary evaporator, and collecting colorless fractions of 8 ml at the temperature of 116-117 ℃/5mmHg by using reduced pressure distillation on the rest to obtain ethyl anthranilate with the yield of 53.2%. Route [2]b: (Synthesis OABHA)

19.6 g (0.49 mol) of sodium hydroxide was dissolved in 80 ml of water, slowly added to 100 ml of ice water containing 15.8 g (0.1 mol) of hydroxylamine sulfate, and 16.52 g (0.1 mol) of o-ammonia was addedAnd (3) ethyl benzoate. Stir at room temperature under nitrogen for 4 hours overnight. Acidification with 25% sulfuric acid in an ice bath resulted in precipitation. Filtering, recrystallizing twice with water, and vacuum drying to obtain light pink powder OABHA. Route [3]: (Synthesis of Complex [ (OABHA) SnBu₂]₂O)

0.6086 g (4 mmol) of the ligand anthranoylhydroxamic acid OABHA was dissolved in a mixture of 120 ml of toluene and 40 ml of absolute ethanol under reflux, and then 0.996 g (4 mmol) of dibutyltin oxide Bu was added₂SnO is refluxed for 6 hours under the protection of nitrogen. After the reaction is finished, evaporating half of the solvent, and evaporating the rest under the vacuum condition to obtain a crude productRecrystallizing with anhydrous ethanol, filtering, collecting, and vacuum drying to obtain [ (OABHA) SnBu₂]₂And O. (3) The application is as follows:

the compound has strong inhibitory effect on human nasopharyngeal carcinoma KB, human gastric cancer BGC-823, human liver cancer Bel-7402, human colon cancer HCT-8, and human leukemia HL-60, and can be used for treating P₃₈₈The inhibition rate of mouse leukemia and A-549 human lung adenocarcinoma tumor cells is strong.

Claims (2)

1. A binuclear aromatic heterocyclic monohydroyl hydroxamic acid dialkyl tin compound is characterized in that the structural general formula is as follows:

r is Et, Bu, Ph; wherein R' is H, Ph; r is a heterocyclic ring

And

and benzene rings substituted by nitro, amino, hydroxyl at different positions.

2. The method for synthesizing a tin compound according toclaim 1, characterized by comprising the steps of:

0.2 mol of the acid RCOOH is dissolved in 2 mol of methanol CH₃OH or 1.334 mol of absolute ethanol C₂H₅In OH, cooling in ice-water bath and stirringSlowly dripping 16.7 ml of concentrated sulfuric acid under stirring, and refluxing for 4 hours. Cooled to 30 ℃, adjusted to PH 9 with 20% sodium carbonate solution, extracted with anhydrous ether, the combined extracts, dried ether extracts over anhydrous magnesium sulfate, shaken and allowed to stand overnight. Filtering to remove desiccant, quickly evaporating diethyl ether and excessive alcohol from the filtrate with rotary evaporator, and collecting the rest fraction by vacuum distillation to obtain ester RCOOR; or

0.1 mol of the acid RCOOH is dissolved in 0.8 mol of absolute ethanol C₂H₅In OH, cooling in ice water bath, slowly dripping 7 ml of concentrated sulfuric acid while stirring, and refluxing for 6 hours. Cooled to 30 ℃, adjusted to PH 9 with 20% sodium hydroxide solution, extracted with toluene, the extracts combined, the toluene extracts dried over anhydrous magnesium sulfate, shaken and left to stand overnight. Filtering to remove desiccant, evaporating the filtrate with rotary evaporator to remove toluene and excessive alcohol, and collecting the rest by vacuum distillation to obtain ester RCOOR (RCOOC)₂H₅)；

24.32 g (0.35 mol) of hydroxylamine hydrochloride were dissolved in 140 ml of methanol by reflux, and 30.86 g (0.55 mol) of potassium hydroxide were dissolved in 100 ml of methanol by the same method. And when the solution and the solution are cooled to 30-40 ℃, pouring the rear solution into the front solution while cooling and shaking, standing for 5 minutes to ensure that the potassium chloride is completely precipitated, and filtering out the precipitate to obtain a methanol solution of hydroxylamine and potassium hydroxide. Adding 0.2 mol of the prepared ester RCOOR _ into the filtrate, stirring for 2 hours to obtain RCONHOK precipitate, filtering, dissolving in a small amount of water, stirring, acidifying with 2N acetic acid until the pH value is 5, stirring for 2 hours, filtering to obtain a crude product, recrystallizing with water twice, and vacuum drying to obtain ligand hydroxamic acid RCONHOH; or

19.6 g (0.49 mol) of sodium hydroxide was dissolved in 80 ml of water, and slowly added to 100 ml of ice water containing 15.8 g (0.1 mol) of hydroxylamine sulfate, and 0.1 mol of ester RCOOR. RTM. was added. Stir at room temperature under nitrogen for 4 hours overnight. Acidification with 25% sulfuric acid in an ice bath resulted in precipitation. Filtering, recrystallizing with water twice, and vacuum drying to obtain ligand hydroxamic acid RCONHOH; (3)

4 mmol of ligand hydroxamic acid RCONHOH is dissolved in a mixture of 120 ml of toluene and 40 ml of absolute ethanol (or 200 ml of a mixture of 3: 1 benzene: methanol) by reflux, and then 4 mmol of tin dihydrocarbyloxide R is added₂"SnO, refluxing for 6 hours. After the reaction is finished, evaporating a half of the solvent, evaporating the rest under the evacuation state to obtain a crude product, recrystallizing by using absolute ethyl alcohol, filtering, collecting, and drying in vacuum to obtain the binuclear aromatic and heterocyclic monoacyl hydroxamic acid dialkyl tin compound [ R [₂”Sn(OR’NOCR)]₂O (when R ═ substituent is-OH, -NH)₂The benzene ring of (a), the whole reaction process needs to be protected by nitrogen).